Bench-Stable Electrophilic Fluorinating Reagents for Highly Selective Mono- and Difluorination of Silyl Enol Ethers

Article abstract of DOI:10.1002/chem.202101499

Efficient methods for the synthesis of fluorinated compounds have been intensively studied, recently. Development of practical fluorinating reagents is indispensable for this purpose. Herein, bench-stable electrophilic fluorinating reagents were synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes. Reagents obtained by replacing one of the NFSI sulfonyl groups with an acyl group led to the highly selective monofluorination of silyl enol ethers with suppression of undesired overreaction, that is, difluorination. On the other hand, reagents bearing electron-withdrawing substituents at NFSI benzenesulfonyl groups efficiently facilitated the difluorination of silyl enol ethers under base-free conditions. Thus, both mono- and difluorinated target materials were prepared from the same substrate.

Full text of DOI:10.1002/chem.202101499

Accepted Article
Accepted Article
Title: Bench-Stable Electrophilic Fluorinating Reagents for Highly
Selective Mono- and Difluorination of Silyl Enol Ethers
Authors: Kohsuke Aikawa, KyoKo Nozaki, Takashi Okazoe, Yuichiro
Ishibashi, and Akiya Adachi
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To be cited as: Chem. Eur. J. 10.1002/chem.202101499
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01/2020

10.1002/chem.202101499
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Bench-Stable Electrophilic Fluorinating Reagents for Highly
Selective Mono- and Difluorination of Silyl Enol Ethers
Akiya Adachi,[a] Kohsuke Aikawa,*[a] Yuichiro Ishibashi,[b] Kyoko Nozaki,[a] and Takashi Okazoe[a,b]
[a]
A. Adachi, Prof. Dr. K. Aikawa,* Prof. Dr. K. Nozaki, and Dr. T. Okazoe
Department of Chemistry and Biotechnology
Graduate School of Engineering
The University of Tokyo
2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-8656, Japan
E-mail: aikawa@g.ecc.u-tokyo.ac.jp
Y. Ishibashi and Dr. T. Okazoe
[b]
Yokohama Technical Center, AGC Inc.
1-1 Suehiro-cho, Tsurumi-ku
Yokohama 230-0045, Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: Efficient methods for the synthesis of fluorinated
compounds have been intensively studied, recently. Development of
practical fluorinating reagents is indispensable for this purpose.
Herein, bench-stable electrophilic fluorinating reagents were
synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes.
Reagents obtained by replacing one of the NFSI sulfonyl groups with
an acyl group led to the highly selective monofluorination of silyl enol
ethers with suppression of undesired overreaction, that is
difluorination. On the other hand, reagents bearing electron-
withdrawing substituents at NFSI benzenesulfonyl groups efficiently
facilitated the difluorination of silyl enol ethers under base-free
conditions. Thus, both mono- and difluorinated target materials were
prepared from the same substrate.
NFSI derivatives remain few in number. For instance, Shibata and
co-workers reported that NFBSI [N-fluoro-(3,5-di-tert-butyl-4-
methoxy)benzene-sulfonimide] as a sterically more demanding
NFSI derivative allows the cinchona alkaloid–catalyzed
fluorination of silyl enol ethers to be performed with higher
enantioselectivity than in the case of NFSI itself, although the
steric hindrance of the former reagent results in decreased
reactivity.[15] The above authors also disclosed that the use of a
sterically less demanding NFSI derivative (Me-NFSI) improves
reactivity in the Lewis acid–catalyzed fluorination of -keto esters,
oxindoles, and malonates.[16] Yang and co-workers independently
reported that in the case of oxindole fluorination,
enantioselectivity and reactivity can be increased through the use
of structure-micro-tuned NFSIs with different substituents on
benzene rings.[17]
On the other hand, fluorinated alkyl groups can act as the
bioisosteres of more polar or less stable functionalities, e.g., the
monofluoromethylene group (–CHF–) is a lipophilic bioisostere of
the secondary alcohol group (–CH(OH)–), while the
difluoromethylene group (–CF2–) can serve as a carbonyl or ether
group mimic.[18] As subtle differences between structures with one
and two fluorine atoms strongly influence bioactivity,[18b] methods
of selectively producing both mono- and difluoromethylene
compounds from the same substrate are highly sought after,
although only few such synthetic methods have been reported.[19–
Introduction
Organofluorine compounds are widely used in the production of
pharmaceuticals and agrochemicals,[1] as the introduction of
fluorine atoms can increase biological activity and enhance
physicochemical properties such as bioavailability, lipophilicity,
and metabolic stability.[2] Consequently, drug discovery research
has recently focused on the establishment of efficient routes to
fluorinated compounds and, hence, on the development of
practical fluorinating reagents. Despite the abundance of
fluorinating reagents reported over the last 30 years,[3] practical
electrophilic fluorinating reagents[4] remain comparatively
unexplored compared to their nucleophilic counterparts.[1b,3f,5]
Among the few commercially available bench-stable electrophilic
21]
To the best of our knowledge, the method of selectively
producing both -mono- and -difluoromethylene carbonyl
compounds form silyl enol ethers as the same substrates has
never been reported. Silyl enol ethers, which are reactive and
easy-to-handle enolate anion equivalents, can be readily
prepared by reliable protocols and smoothly react with
electrophilic fluorinating reagents under mild base-free
conditions.[22] Herein, we report the synthesis of bench-stable
electrophilic fluorinating reagents as NFSI substitutes and use
them to realize the highly selective mono- and difluorination of silyl
enol ethers derived from ketones (Scheme 1c). As the order of
fluorinating power of reagents is shown in Scheme 1b, reagents
obtained by replacing one of the NFSI sulfonyl groups with an acyl
group led to the highly selective monofluorination of silyl enol
ethers with suppression of difluorination (Scheme 1c left).[23]
Moreover, reagents bearing electron-withdrawing substituents at
fluorinating reagents, one can mention SelectfluorTM [6]
N-
,
fluoropyridinium salts,[7] and N-fluorobenzenesulfonimide
(NFSI),[8] which have been widely used in both discovery and
manufacturing processes of the pharmaceutical industry (Scheme
1a). Our research group is interested in the development of
practical fluorinating reagents, especially those featuring the NFSI
backbone and an N–F covalent bond,[9–13] as the introduction of
various substituents on benzene rings and the replacement of
sulfonyl groups with other moieties is expected to control both
reactivity and fluorination selectivity. However, despite the recent
progress in NFSI-based synthetic methods,[14] the developed
1
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NFSI benzenesulfonyl groups efficiently difluorinated silyl enol
ethers (Scheme 1c right).[24,25]
Table 1. Synthesis of N–F reagents with N–F covalent bonds using F2.[a]
Scheme 1. Design of bench-stable electrophilic fluorinating reagents and their
application to mono- and difluorination of silyl enol ethers.
[a] Yield was determined by 19F NMR analysis using 2,3,5,6-tetrafluoro-p-xylene
as an internal standard. [b] Reactions of lithium salts 1’ were carried out without
NaF. [c] Non-essential hydrogen atoms were omitted. Angles: S–N–F = 105.83°,
F–N–C = 106.76°, C–N–S = 118.54°. Bond lengths” N–F = 1.417 Å, N–S = 1.756
Å, N–C = 1.444 Å, C=O = 1.204 Å.
Results and Discussion
At the onset of our research, N-fluoro-N-(sulfonyl)amides 2[26]
were prepared as electrophilic reagents for selective
monofluorination by reacting N-(sulfonyl)amide
1 or the
corresponding lithium salt 1’ with N2-diluted F2 (2 vol%) (Table
1).[17a] In the reaction of 1, NaF (3 eq.) was added to trap in situ
generated HF. The fluorination of N-(sulfonyl)amides (1a–c) with
an electron-withdrawing trifluoromethyl substituent attached to
the benzoyl group was performed in acetonitrile at 0 °C, and the
corresponding products 2a–c were obtained in 10–68% yields.
However, the transformation of phenyl group–bearing 1d to 2d
was not successful because of the competing electrophilic
fluorination of the benzene ring. Additionally, tert-butyl group–
bearing 2e could not be obtained under the same conditions.
Fortunately, lithium salts 1’b–e reacted with F2 more efficiently to
afford the desired products 2b–e in moderate to good yields, while
the yield of 2a was slightly lower. m,m-Difluoro and -dichloro
derivatives 1’f–g afforded products 2f–g in 75 and 55% yields,
Despite the numerous successful examples of monofluorination
at the α-position of the carbonyl group,[23] the selective
monofluorination of monosubstituted silyl enol ethers remains
underexplored.[27,28] To bridge this gap, we investigated the
selective monofluorination of a model silyl enol ether (3a) with 2
(1.2 eq) (Table 2), revealing the formation of monofluorinated
ketone 4a, its silyl enol ether 5a, and difluorinated ketone 6a by
19F NMR analysis of the reaction mixture. The control experiment,
i.e., the fluorination of 3a with NFSI, also afforded the above
products, although the monofluorination selectivity was low and
6a was obtained as the major product because of overfluorination.
The use of different reaction conditions, e.g., lower reaction
temperatures and reduced NFSI loadings, did not increase
monofluorination selectivity. In stark contrast, fluorination with 2a
afforded monofluorinated 4a in 83% yield, with the mono- to
difluorinated product ratio reaching 98:2. Reagents 2b–c, bearing
para- and ortho-trifluoromethyl substituents, respectively,
featured lower selectivity and reactivity. Fluorination could also be
achieved with electron-withdrawing group–free 2d and with
aliphatic group–bearing 2e, although insufficient fluorinating
power was observed in both cases. The m,m-difluoro and -
dichloro derivatives 2f–g showed sufficient reactivity while
featuring a slightly lower selectivity than 2a. Furthermore, the
introduction of electron-withdrawing substituents at the
benzenesulfonyl group instead of the benzoyl group slightly
decreased selectivity (2i–j). According to these results, 2a with
m,m-bis(trifluoromethyl) substituents was concluded to be most
respectively.
The
introduction
of
electron-withdrawing
substituents at both benzoyl and benzenesulfonyl moieties
destabilized the corresponding product (2h) and promoted its
decomposition under the reaction conditions. Lithium salts with
electron-withdrawing
substituents
attached
to
the
benzenesulfonyl group and not to the benzoyl group (1’i–j)
reacted to furnish the desired products 2i–j in 52 and 70% yields,
respectively. All fluorinating reagents 2 were readily purified by
silica-gel column chromatography and preserved as bench-stable
white solids. The structure of 2a, featuring a trigonal pyramidal
geometry at the nitrogen atom, was unambiguously determined
by single-crystal X-ray diffraction. The N–F bond length in 2a
(1.417 Å) was almost equal to those in previously reported N–F
reagents with covalent N-F bonds.[15]
2
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suitable for the highly selective monofluorination of silyl enol
ethers 3a.
selectivity declined with progressing NFSI consumption, and an
approximately equimolar mixture of mono- and difluorinated
products was obtained at the time of >80% NFSI conversion. In
sharp contrast, the high selectivity of monofluorination was
maintained regardless of the reaction progress for 2a.
Table 2. Screening of N–F reagents for monofluorination.[a]
Next, we studied the substrate scope for the reaction of silyl
enol ethers 3 with the optimized reagent (2a) under standard
reaction conditions (Table 3). Silyl enol ethers prepared from five-,
six-, and seven-membered cyclic ketones were smoothly
transformed to monofluorinated products with high mono-
selectivity in good to excellent yields (4a–f). The high mono-
selectivity observed for five-membered substrates 3b–e is
particularly noteworthy, as the corresponding monofluorinated
products have more acidic -protons and are more easily
enolized to cause difluorination. The reactions of heterocycles
3g–h prepared from 1-chromanone and 1-thiochromanone
produced the desired products (4g–h) in moderate yields.
Moreover, 3i–n obtained from acyclic ketones were fluorinated
with excellent mono-selectivity, even at the reactive benzylic
position characterized by easy enolization (4n). Although a lower
mono-selectivity was observed for the cyclic 3o, no α,α’-
difluorination was observed.
Table 3. Scope of silyl enol ethers for monofluorination.[a]
[a] Conditions: 3a (0.10 mmol) and 2 (0.12 mmol) in CH2Cl2 (1.0 mL) at 25 °C
for 24 h. Yields were determined by 19F NMR analysis using 2,3,5,6-tetrafluoro-
p-xylene as an internal standard.
Scheme 2. 2a vs. NFSI: Reactivity and selectivity for monofluorination.
[a] Conditions: 3 (0.10 mmol) and 2a (0.12 mmol) in CH2Cl2 (1.0 mL) at 25 °C
for 24 h. Yields were determined by 19F NMR analysis using 2,3,5,6-tetrafluoro-
p-xylene as an internal standard.
The time course of the fluorinations of 3a with 2a and NFSI was
monitored in CD2Cl2 at 25 °C (Scheme 2), and reactivities were
assessed by comparing fluorinating reagent conversions
(Scheme 2a). Treatment with 2a resulted in a conversion of >70%
after 18 h, despite the lower reactivity of this reagent compared to
that of NFSI. Monofluorination selectivity was evaluated as the
ratio of monofluorinated product (4a + 5a) and difluorinated
product (6a) contents (Scheme 2b). In the case of NFSI,
The reaction mechanism was probed by examining the
fluorination and protonation of monofluorinated silyl enol ether 5a.
The fluorination of 5a by both 2a and NFSI was almost complete
within 2 h, i.e., was faster than that of 3a in Scheme 2a (Scheme
3, Eq. 1). For the difluorination of 1,3-dicarbonyl compounds with
3
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NFSI, the second fluorination step is known to be faster than the
first one.[29] Notably, 5a was not protonated upon treatment with
1a, and 5a was completely recovered (Scheme 3, Eq. 2). In
contrast, the addition of dibenzenesulfonimide caused the
protonation of 5a to afford 4a in 54% yield, as
dibenzenesulfonimide is a stronger Brønsted acid than 1a.[30]
other hand, the oxygen anion of Y−, which possesses a higher
affinity to the silyl group, can efficiently promote desilylation to
inhibit deprotonation (Int to 4a).
According to the mechanism proposed for selective
monofluorination, we envisioned that N–F reagents 7 bearing
electron-withdrawing substituents on benzenesulfonyl groups,
which in situ produce the more Lewis-acidic silyl cation, can
directly difluorinate silyl enol ethers without a base. Hence, the
difluorination of silyl enol ether 3i as an acyclic substrate was
initially explored, as the deprotonation of the corresponding
monofluorinated product was expected to be slower than that of
cyclic 3a. Reactivity was evaluated using 2.2 equivalents of 7 in
dichloroethane at 50 °C (Table 4). Importantly, the position of
substituents on the benzenesulfonyl group strongly affected
difluorination
reactivity.
Reagent
7a
bearing
3,5-
bis(trifluoromethyl) substituents efficiently afforded the
difluorinated product 6i (91% yield) as the sole fluorinated product.
However, the incorporation of 2,4-bis(trifluoromethyl) substituents
(7b) decreased reactivity under the same conditions, probably by
increasing steric hindrance in the sulfonimide anion generated in
situ. Reagent 7c with a less sterically demanding methyl group
instead of the phenyl group was also inferior to 7a. Moreover,
reagent 7d possessing the pentafluorophenyl group did not
outperform 7a. In the case of 7e with a 4-trifluoromethyl
substituent on the other benzene ring, the reaction was completed
within 6 h, although the problem of low yield in the synthesis of 7e
itself still remains. The introduction of electron-withdrawing
groups at both benzene rings of NFSI is known to induce the
cleavage of N–S bonds under the conditions of treatment with F2
gas.[17a,b] Notably, when 4.0 equivalents of NFSI and a longer
reaction time were used, products 4i and 6i were obtained in 23%
and 53% yields, respectively, and the reaction did not proceed to
completion.
Scheme 3. Fluorination and protonation of monofluorinated silyl enol ether 5a.
Scheme 4 presents the mechanism here we propose for
selective monofluorination with 2a and partial difluorination with
NFSI. In the first step, the reaction of 3a with the N–F reagent
generates intermediate Int, which is subsequently desilylated to
afford the monofluorinated product 4a. On the other hand, the
deprotonation of Int followed by the second fluorination of
fluorinated-enol ether 5a furnishes the difluorinated product 6a.
As described in Scheme 3, Eq. 1, once 5a is in situ produced
through deprotonation of Int, the second fluorination proceeds
faster than the first one both with 2a and NFSI. Accordingly, the
selective monofluorination with 2a should not originate from the
second fluorination step but steps before reaching 5a. As
mentioned in Scheme 3, Eq. 2, the reverse reaction of 5a back to
Int, that is the protonation of 5a providing 4a through Int was
observed with (PhSO2)2NH (ZH in Scheme 4) but not with 1a (YH).
Thus, here we can conclude that, in case of 2a, the deprotonation
of Int to 5a does not almost take place. In the deprotonation of Int
to give 5a, the more Lewis-acidic ZSi silyl cation can activate the
carbonyl group more than the YSi cation, thus facilitating
deprotonation at the -position by the counter anion Z−.[30] On the
Table 4. Screening of N–F reagents for difluorination.[a]
[a] Conditions: 3h (0.10 mmol) and 7 (0.22 mmol) in (CH2Cl)2 (1.0 mL) at 50 °C
for 24 h. Yields were determined by 19F NMR analysis using 2,3,5,6-tetrafluoro-
p-xylene as an internal standard. [b] Reaction time = 6 h. [c] Reaction time = 48
h.
Scheme 4. Plausible fluorination mechanism.
4
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Reagent 7a, prepared by treatment with F2 in much higher yield
than 7e, was successfully applied to the difluorination of various
silyl enol ethers 3 without a base (Table 5). (Hetero)cyclic silyl
enol esters 3a–h were suitable substrates, affording the
corresponding difluorinated products 6a–h at 25 or 50 °C within 4
h, regardless of the electronic properties and position of
substituents on the benzene rings. Additionally, acyclic substrates
3i–n were efficiently converted into the desired difluorinated
products 6i–n, although longer reaction times were required than
in the case of cyclic substrates. The reaction of aliphatic substrate
3o was characterized by decreased di-selectivity.
Finally, we examined the selective mono- and difluorination of
a silyl enol ether (3p) directly prepared from a biologically active
compound, oxcarbazepine[31] (Scheme 5). The reactions of 3p
with 2a and 7a highly selectively afforded mono- and difluorinated
products 4p and 6p, respectively. The result shows that these
reagents are applicable to late-stage protocol toward the
introduction
of
fluorine
atoms
into
targets
with
biological/pharmacological activities.[32]
Conclusion
In summary, we have developed bench-stable electrophilic
fluorinating reagents by replacing one of the NFSI sulfonyl groups
with an acyl group to enable the highly selective monofluorination
of silyl enol ethers and inhibit undesired difluorination. In this case,
the suppression of the deprotonation of monofluorinated products
generated in situ was the key to selective monofluorination.
Furthermore, the developed bench-stable NFSI derivatives with
electron-withdrawing substituents at benzenesulfonyl groups
could more efficiently (compared to the well-explored NFSI)
facilitate the difluorination of silyl enol ethers without a base.
These results clearly indicate that mono- and difluorinated
compounds can be selectively produced from the same starting
material using reagents with a modified NFSI backbone. Further
studies toward the development of unique and practical
electrophilic fluorinating reagents that can be prepared using F2
gas are in progress in our laboratory.
Table 5. Scope of silyl enol ethers for difluorination.[a]
Experimental Section
Typical procedure of monofluorination. Preparation of 2-fluoro-1-
tetralone 4a. To a mixture of fluorinating reagent 2a (49.8 mg, 0.12 mmol,
1.2 equiv.) in CH2Cl2 (0.1 M, 1.0 mL) was added silyl enol ether 3a (21.8
mg, 0.10 mmol, 1 equiv.) at room temperature under N2 atmosphere. After
stirring for 24 h at 25 °C, the yield and selectivity (85%, mono/di = 98/2)
were determined by 19F NMR spectroscopy analysis using 2,3,5,6-
tetrafluoro-p-xylene as an internal standard. The reaction mixture was
directly loaded onto a silica-gel column (n-hexane/EtOAc = 7/1) to give the
compound (11.7 mg, 80% yield) as a white solid. The product (4a) is known
and the following data are identical to those given in corresponding
literature[33]; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 1H), 7.53 (t,
J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 5.15 (ddd,
J = 48.0, 12.8, 5.2 Hz, 1H), 3.13 (dd, J = 8.8, 4.4 Hz, 2H), 2.30-2.63 (m,
2H); 19F NMR (376 MHz, CDCl3) δ -190.2 (d, J = 52.3 Hz, 1F).
[a] Yield was determined by 19F NMR analysis using 2,3,5,6-tetrafluoro-p-xylene
as an internal standard. [b] At 25 °C for 4 h in CH2Cl2. [c] At 50 °C for 4 h in
(CH2Cl)2. [d] At 50 °C for 2 h in (CH2Cl)2. [e] At 50 °C for 24 h in (CH2Cl)2. [f] At
25 °C for 96 h in CH2Cl2. [g] 7a (2.5 eq.), at 50 °C for 72 h in (CH2Cl)2.
Typical procedure of difluorination. Preparation of 2,2-difluoro-1-
phenyl-1-propanone 6i. To a mixture of fluorinating reagent 7a (49.6 mg,
0.11 mmol, 2.2 equiv.) in (CH2Cl)2 (0.1 M, 0.5 mL) was added silyl enol
ether 3i (10.3 mg, 0.05 mmol, 1 equiv.) at room temperature under N2
atmosphere. After stirring for 24 h at 50 °C, the yield and selectivity (91%,
mono/di = 1/>99) were determined by 19F NMR spectroscopy analysis
using 2,3,5,6-tetrafluoro-p-xylene as an internal standard. The reaction
mixture was directly loaded onto a silica-gel column (n-hexane/EtOAc =
20/1) to give the compound (7.2 mg, 85% yield) as a yellow oil. The product
(6i) is known and the following data are identical to those given in
corresponding literature[34]; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4
Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 1.90 (t, J = 17.6
Hz, 3H); 19F NMR (376 MHz, CDCl3) δ -92.7 (q, J = 17.2 Hz, 2F).
Scheme 5. Selective mono- and difluorination of a biologically active compound
achieved using reagent control.
5
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Acknowledgements
We thank Mr. Kazuki Matsumura (AGC Inc.) for help with X-ray
analysis.
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Keywords: electrophilic fluorinating reagent • fluorine gas •
NFSI • monofluorination • difluorination
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10.1002/chem.202101499
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Bench-stable electrophilic fluorinating reagents [N-fluorobenzenesulfonimide (NFSI) analogues] were synthesized using F2 gas.
Reagents obtained by replacing one of the NFSI sulfonyl groups with an acyl group led to the highly selective monofluorination of silyl
enol ethers with suppression of difluorination. On the other hand, reagents bearing electron-withdrawing substituents at NFSI
benzenesulfonyl groups efficiently facilitated the difluorination of silyl enol ethers. Reagent control allowed both mono- and difluorinated
targets to be selectively produced from the same starting materials.
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