Methyl NFSI: Atom-economical alternative to NFSI shows higher fluorination reactivity under Lewis acid-catalysis and non-catalysis

Article abstract of DOI:10.1039/c5gc02612a

Me-NFSI was first reported in 1994. Despite its atom-economical structure and similarity to a well-explored fluorinating reagent, NFSI, Me-NFSI has not appeared in the literature in over 20 years. We disclose that Me-NFSI is more effective for the fluorination of active methines under Lewis acid-catalysis and non-catalysis than NFSI.

Full text of DOI:10.1039/c5gc02612a

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Methyl NFSI: atom-economical alternative to
NFSI shows higher fluorination reactivity under
Lewis acid-catalysis and non-catalysis†
Cite this: DOI: 10.1039/c5gc02612a
Received 30th October 2015,
Accepted 18th November 2015
Kazunobu Fukushi,a Satoru Suzuki,a Tomohiro Kamo,a Etsuko Tokunaga,b
DOI: 10.1039/c5gc02612a
Yuji Sumii,a Takumi Kagawa,c Kosuke Kawadac and Norio Shibata*a,b
www.rsc.org/greenchem
Me-NFSI was first reported in 1994. Despite its atom-economical
structure and similarity to a well-explored fluorinating reagent,
NFSI, Me-NFSI has not appeared in the literature in over 20 years.
We disclose that Me-NFSI is more effective for the fluorination
of active methines under Lewis acid-catalysis and non-catalysis
than NFSI.
Fig. 1 Shelf-stable N–F type electrophilic fluorination reagents.
Introduction
Direct electrophilic fluorination of organic molecules is surely tinuously been employed to discover new reactions and valu-
one of the most straightforward methods for the synthesis able compounds with expected properties in both academia
of organofluorine compounds which are sought after in and industry, they suffer from an intrinsic drawback, namely
the fields of pharmaceuticals, agrochemicals and specialty poor atom-economical transformation, limiting large-scale
materials.1,2 The early days of electrophilic fluorination were preparations in process chemistry. Electrophilic fluorination
problematic since there was a lack of suitable reagents for this reagents, many of which have been reported in the literature,
purpose, and highly toxic gaseous fluorine (F2), explosive can fulfil the atom-economical and environmentally-friendly
fluoro perchlorite (FClO3), trifluoromethyl hypofluorite needs of modern chemistry to serve society’s needs.8 However,
(CF3OF), or expensive xenon difluoride (XeF2) were being used. we noticed that N-fluoromethanesulfonimide (F–N(SO2Me)2,
Since the initial report by Barnette in the mid-1980s claiming Me-NFSI) has been poorly explored despite its atom-economi-
that N-fluorosulfonamide 1 is useful for the direct electrophilic cal structure (Fig. 1).9
fluorination of carbanions,3 research on the development of
Me-NFSI was first reported by Bohlmann in 1994 during the
N–F type shelf-stable reagents for electrophilic fluorination electrophilic fluorination of carbanions but there were only
has been widely spurred worldwide,4 including by our group.5 three examples of the reaction with sodium malonate, lithium
Among the many kinds of reagents developed,2,4 chloro- acetylide and anthracenyl lithium.9 However, the two methyl
methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetra- groups of Me-NFSI might be a problem due to their acidity
fluoroborate) (Selectfluor®)6 and N-fluorobenzenesulfonimide under basic conditions. On the other hand, it is reasonable to
(NFSI)7 have become two of the most popular reagents in this expect that higher basicity of sulfonyl oxygens of Me-NFSI than
field due to their accessibility, suitable reactivity and stability regular NFSI will bring about a desirable outcome under acid
(Fig. 1). While the two reagents are very useful and have con- catalysis. Moreover, the water solubility of methanesulfoni-
mide, HN(SO2Me)2, a residue that forms after fluorination, is
very beneficial from a practical point of view, since it is easily
washed out during the work-up process. In this paper, we dis-
close herein that Me-NFSI is an atom-economical alternative to
NFSI, and has notable advantages over NFSI in the electro-
philic fluorination of active methine compounds including β-keto
esters, oxindoles, and malonates under Lewis acid-catalysis.
More interestingly, the reaction of β-keto esters also proceeds
smoothly without any catalyst providing the corresponding
aDepartment of Nanopharmaceutical Sciences, Nagoya Institute of Technology (NIT),
Gokiso, Showa-ku, Nagoya 466-8555, Japan. E-mail: nozshiba@nitech.ac.jp;
Fax: +81-52-735-7543
bDepartment of Frontier Materials, Nagoya Institute of Technology (NIT), Gokiso,
Showa-ku, Nagoya 466-8555, Japan
cTOSOH F-TECH, Inc., 4988, Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan.
Fax: +81-834-62-1303; Tel: +81-834-62-1300
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5gc02612a
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fluorinated compounds in good to high yields. In particular, the difference was not as large as that for 2b (Table S2†). The
methanol is the best choice of solvent. Water is also useful as rapid reaction by Me-NFSI can be explained by the activation
a solvent for fluorination by Me-NFSI.
of Me-NFSI via the coordination of its sulfonyl oxygens with
Ti(IV), which was ascertained by 19F-NMR experiments. Namely,
the chemical shift of Me-NFSI is −44.381 (internal standard
was PhCF3 −63.000, CD2Cl2) which shifted to −44.400 ppm
after the addition of 1 equiv. of Ti(OiPr)4 (see Fig. S4 and S5†).
On the other hand, the chemical shift of NFSI remained
constant at −38.331 ppm, independent of the existence of
Ti(OiPr)4 (see Fig. S6 and S7†). Interestingly, different chemical
shifts were also observed depending on the amount of
Ti(OiPr)4. The original −44.425 ppm (Me-NFSI, in CDCl3) was
shifted to −44.499 ppm with 0.5 equiv. of Ti(OiPr)4, and to
−44.462 ppm with 1.0 equiv. of Ti(OiPr)4 (Fig. S8–S10†). These
results would suggest that Ti(OiPr)4 coordinates Me-NSFI sulfo-
nyl oxygen atoms, as depicted in Fig. 3a and b.
Results and discussion
Me-NFSI is easily prepared in two steps from the reaction of
commercially available methanesulfonyl chloride according to
Bohlmann’s procedure.9 Namely, methanesulfonyl chloride
was treated with NH4Cl and NaOH in aqueous acetone at 0 °C
to provide HN(SO2Me)2 in 61% yield.10 HN(SO2Me)2 was fluori-
nated using 10% gaseous fluorine in nitrogen in the presence
of NaF in MeCN at −40 °C to furnish Me-NFSI in 76% yield.
The Me-NFSI obtained is a shelf-stable colorless solid (mp =
48–49 °C; CH2Cl2) (Scheme 1).
Initially, due to the difference in basicity of the sulfonyl
oxygens in NFSI and Me-NFSI, we envisaged that fluorination
under acid-catalysis using Me-NFSI would be clearly advan-
tageous than the use of NFSI. Thus, the initial comparison of
the fluorination of β-keto esters 2a,b by Me-NFSI and NFSI was
examined under Ti(OiPr)4 catalysis at room temperature in
CH2Cl2. This expectation was realized in practice, in particular
In order to further discuss the higher reactivity achieved by
Me-NFSI, DFT calculations11 were attempted next. The charge
distributions of fluorine (F) on Me-NFSI, NFSI and their tita-
nium complexes were calculated (DFT/B3LYP/6-31G*) (Fig. 3c–f,
also see Table S5†). In Me-NFSI and NFSI, the charge distri-
butions of the F were almost similar (Fig. 3c vs. e). On the
other hand, the charge distribution of each F in titanium com-
plexes is rather different, and F in Me-NFSI is more positive
than that of NFSI (Fig. 3d vs. f). These computed results
suggest that the reactivity of Me-NFSI seems to be higher than
that of NFSI when it is complexed with Ti(IV).
t
the fluorination of sterically demanding Bu ester 2b (Fig. 2
and Table S1 in the ESI†). The fluorination of 2b by NFSI gave
product 3b in 20% yield after 10 min, and the yield of 3b
gradually increased to 80% over 24 hours. On the other hand,
Me-NFSI produced 3b in 90% yield within only 5 min. A
similar rate-acceleration tendency by Me-NFSI over NFSI was
also observed for the fluorination of methyl ester 2a, although
The acid-catalyzed fluorination by Me-NFSI was found to be
quite general for a series of β-keto esters 2a–r (Table 1). The
t
substrates with sterically demanding Bu ester 2b and 1-ada-
mantyl ester 2c gave similar high yields of 3b,c as methyl ester
2a within 3 h. The reaction was also adapted to substituted
indanone derivatives 2d–h with electron-donating Me and
MeO, and electron-withdrawing Br and Cl groups on the
benzene ring. Tetralone derivatives 2i–k were also fluorinated
in good to excellent yields with a slightly extended reaction
time. A benzosuberone derivative having a 7-membered ring 2l
was also converted smoothly to the desired product 3l in 92%
yield, although a longer reaction time (24 h) was required. The
fluorination of cyclopentanone carboxylates 2m,n, cyclohexe-
Scheme 1 Preparation of Me-NFSI.
Fig. 2 GC-analysis of titanium-catalyzed fluorination. Reaction con-
ditions: 2b (1.0 mmol), Me-NFSI or NFSI (1.2 equiv.), Ti(OiPr)4 (10 mol%),
CH2Cl2 (10 mL, 0.1 M), rt.
Fig. 3 (a, b) Proposed activations of Me-NFSI by Ti(OiPr)4. (c–f) B3LYP/
6-31G* atomic charges of fluorine in Me-NFSI and NFSI for the com-
plexes with Ti(IV): electrostatic, Mulliken ( ), and Natural [ ].
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Table 1 Lewis acid-catalyzed fluorination of active methine com-
pounds by Me-NFSIa
Table 2 Fluorination of malonates 6 under Lewis acid-catalysisa
Entry
6
R
R1
7
Yieldb (%)
1
2
3
4
6a
6b
6c
6d
Et
Et
Et
Bn
Me
Ph
Bn
Bn
7a
7b
7c
7d
91
52
77
51
a Reaction conditions: 6 (0.3 mmol), Me-NFSI (2.0 equiv.), Ti(OiPr)4
(20 mol%), toluene (3 mL, 0.1 M), reflux. b Isolated yield.
Table 3 Scope of fluorination of β-keto esters 2 by Me-NFSIa
Entry
2
n
R1
R2
R3
3
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1
1
1
1
1
1
1
1
1
1
1
2
2
2
3
1
1
Me
Me
Me
Me
tBu
1-Ad
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a 24
3a 24
49c (toluene)
63c (CH2Cl2)
3a
3a
4
1
92c (THF)
96 (98c)
3b 12
3c 24
86
69
90
98
66
83
86
91
Me
OMe
OMe OMe 3f
3d
3e
4
4
8
8
9
10
11
12
13
14
15
16
17d
H
H
H
H
Cl
H
H
H
Cl
Br
H
3g
3h 12
3i
24
12
OMe 3j
85
90
35
H
H
H
H
3k 24
a Reaction conditions:
2 or 4 (0.3 mmol), Me-NFSI (1.2 equiv.),
3l
3a
24
4
Ti(OiPr)4 (10 mol%), CH2Cl2 (3 mL, 0.1 M), rt. b 1.0 equiv. of Ti(OiPr)4
was used.
2a
2a
96c (H2O)
81c (H2O)
3a 30
a Reaction conditions: 2 (0.3 mmol), Me-NFSI (1.2 equiv.), MeOH
(3 mL, 0.1 M), rt. b Isolated yield. c 0.1 mmol of 2a was used and yield
was determined by GC. d NFSI was used instead of Me-NFSI.
none carboxylate 2o, cycloheptanone 2p and acyclic β-keto
esters 2q,r was comparatively slower than the benzene-attached
cyclic substrates providing the corresponding fluorinated pro-
ducts 3m–r in low to moderate yields (18–67%). The fluorina-
tion by Me-NFSI under acid-catalysis is also effective for the and 2). Both the yield and reaction time were dramatically
reaction of oxindole derivatives12 4a–e independent of the improved, exceeding 90% (entries 3 and 4). In particular, in
nature of substitutions at the 3- and 5-positions providing MeOH, 3a was obtained in 96% (98%) yield in 1 h. Substrate
fluorinated oxindoles 5a–e in 74–92% yields.
generality for fluorination by Me-NFSI in MeOH under catalyst-
We next examined the fluorination of malonates 6a–d free conditions was next investigated. As shown in Table 3, a
(Table 2). Unfortunately, fluorination was not effective when series of β-keto esters 2b–l were smoothly fluorinated by Me-
β-keto esters were used. After a brief optimization of the reac- NFSI almost independent of the nature of the ester moiety or
tion, the conditions consisting of 20 mol% Ti(OiPr4), 2 equiv. substitution on the aryl group, while a longer reaction time
of Me-NFSI in toluene at reflux temperature furnished fluori- was required for substrates with sterically demanding esters,
nated malonates 7a–d in satisfactory yields (51–91%).
electron-withdrawing substituents on the aryl moiety and tetra-
The fluorination of 2a by Me-NFSI was further attempted lone derivatives (entries 5–14). Benzosuberone 1l was fluori-
under catalyst-free conditions (Table 3). To our surprise, fluori- nated in the absence of catalysts in 35% yield (entry 15). It
nation proceeded without catalysis to provide 3a in good to should be noted that the reaction proceeded very smoothly
high yields (49–98%). In toluene, 49% of 3a was obtained after even in water to provide 3a in 96% yield (entry 16), while NFSI
24 h, but this increased to 63% in CH2Cl2 for 24 h (entries 1 resulted 81% yield after 30 h (entry 17). The difference
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(Platform for Drug Discovery, Informatics, and Structural Life
Science) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), and the Japan Agency for
Medical Research and Development (AMED), a JSPS Grand-in-
Aid for Scientific Research (B) (25288045), and the Koayashi
International Foundation. We also thank Mr Satoru Mori in
NIT for the computations in Fig. 3. A part of MeNFSI is a gift
from TOSOH F-TECH, Inc.
Notes and references
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Fig. 4 GC-analysis of fluorination in MeOH. Reaction conditions: 2a
(0.2 mmol), Me-NFSI or NFSI (1.2 equiv.), MeOH (4 mL, 0.05 M), −40 °C
to rt. Each reaction was repeated four times under the same conditions
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observed is due to the higher solubility of Me-NFSI in water
than NFSI. This is also a clear advantage of Me-NFSI.
To ascertain the distinct benefit of Me-NFSI over NFSI for
fluorination of 2 under catalyst-free conditions, the reaction of
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appears to be a clear advantage in using Me-NFSI over NFSI as
a fluorination reagent, i.e., over 80% of 3a was observed by Me-
NFSI, while about 68% of 3a was produced by NFSI.
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Conclusions
In conclusion, we demonstrated that Me-NFSI is an atom-eco-
nomical alternative to conventional NFSI. Under Lewis acid-
catalysis, the fluorination of active methine compounds by Me-
NFSI is much faster than that by well-explored NFSI. A variety
of β-keto esters, oxindoles and malonates were smoothly
reacted with Me-NFSI providing fluorinated compounds in
good to high yields. More interestingly, Me-NFSI is also useful
for electrophilic fluorination under catalyst-free conditions in
MeOH. H2O is also useful for catalyst-free fluorination by Me-
NFSI. Practical uses may be possible by taking advantage of its
excellent reactivity and the water solubility of its by-product,
HN(SO2Me)2. Rapid reactions by Me-NFSI are also attractive for
applications of 18F-chemistry, since 18F-NFSI has already been
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in due course.
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This research is partially supported by the Platform Project
for Supporting in Drug Discovery and Life Science Research
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