2-(Pyridinium-1-yl)-1,1-bis(perfluoroalkylsulfonyl)ethan-1-ide: A Practical Reagent for Synthesis of Strongly Acidic 1,1-Bis(perfluoroalkylsulfonyl)alkanes

Article abstract of DOI:10.1002/chem.201700515

On mixing (R_fSO₂)₂CH₂ (R_f=perfluoroalkyl), paraformaldehyde, and substituted pyridines, a three-component reaction proceeded smoothly to give unusual zwitterions bearing both pyridinium and stabilized carbanion moieties in good to excellent yields. Of these, 2-fluoropyridinium derivatives rapidly dissociated in acetonitrile to give equilibrium mixtures of the zwitterions and (R_fSO₂)₂C=CH₂/2-fluoropyridine, as confirmed by detailed variable-temperature NMR studies. The dynamic behavior of such 2-fluoropyridinium compounds allows them to be used as shelf-stable, easy-to-handle sources of (R_fSO₂)₂C=CH₂. With these reagents, strongly acidic carbon acids (R_fSO₂)₂CHR were synthesized, which served as a new type of acid catalysts. Moreover, C?C bond-forming reactions with a ketene silyl acetal proceeded efficiently with Tf₂C=CH₂ generated in situ.

Full text of DOI:10.1002/chem.201700515

A Journal of
Accepted Article
Title: 2-(Pyridinium-1-yl)-1,1-bis((perfluoroalkyl)sulfonyl)ethan-1-
ide: a practical reagent for synthesis of strongly acidic 1,1-
bis((perfluoroalkyl)sulfonyl)alkanes
Authors: Hikaru Yanai, Ryuta Takahashi, Yoichi Takahashi, Akira
Kotani, Hideki Hakamata, and Takashi Matsumoto
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201700515
Link to VoR: http://dx.doi.org/10.1002/chem.201700515
Supported by

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
2-(Pyridinium-1-yl)-1,1-bis((perfluoroalkyl)sulfonyl)ethan-1-ide: a
practical reagent for synthesis of strongly acidic 1,1-
bis((perfluoroalkyl)sulfonyl)alkanes
Hikaru Yanai,*[a] Ryuta Takahashi,[a] Yoichi Takahashi,[a] Akira Kotani,[a] Hideki Hakamata,[a] and Takashi
Matsumoto*[a]
Dedicated to Professor Takeo Taguchi on the occasion of his 70th birthday.
Abstract: By mixing (RfSO2)2CH2 (Rf
=
perfluoroalkyl),
In this carbon acid structure, the third substituent “R” makes
the acidity tunable and endows additional, unique properties. This
structural feature is an advantage for the development of novel
strong acids. For instance, in several synthetic reactions including
the Mukaiyama aldol and related reactions, higher catalytic
performance of Tf2CHR over conventional TfOH and Tf2NH has
been reported by us7,8, Yamamoto and Ishihara,9 and List.10
However, flexible molecular design for the carbon acid catalysts
were still difficult owning to a lack of general and effective
synthetic methods.11 For example, -alkylation reactions of
commercially available bis(triflyl)methane 1a (Tf2CH2) with alkyl
halides gave unsatisfactory results owning to the remarkably low
nucleophilicity of the bis(triflyl)methanide ion.11a To overcome the
situation, we previously reported an addition reaction of neutral
nucleophile “H–Nu” with in-situ generated Tf2C=CH2 2a to give the
acid “Tf2CHCH2Nu”. Since highly electrophilic 2a was easily
hydrolyzed into Tf2CH2 1a and formaldehyde, two methods for the
in-situ generation of 2a were developed as follows: 1) self-
promoting condensation of 1a and formaldehyde12 and 2) the
retro-Michael reaction of easily available Tf2CHCH2CHTf2 313
(Eqns. 1 and 2). The latter method was successfully applied to the
reactions with neutral nucleophiles such as electron-rich
arenes13a and 1,3-dicarbonyls13b to give the corresponding carbon
acids, which worked as effective acid catalysts.7,13a
paraformaldehyde, and substituted pyridines, a three-component
reaction proceeded smoothly to give unusual zwitterions bearing both
pyridinium and stabilized carbanion moieties in good to excellent
yields. Of these, 2-fluoropyridinium derivatives rapidly dissociated in
acetonitrile to give equilibrium mixtures of the zwitterions and
(RfSO2)2C=CH2/2-fluoropyridine,
as
confirmed
by
detailed
temperature-variable NMR studies. The dynamic behavior of such 2-
fluoropyridiniums prompted us to examine their utility as shelf-stable,
easy-to-handle (RfSO2)2C=CH2 sources. With these reagents, we
successfully synthesized strongly acidic carbon acids (RfSO2)2CHR,
which served as a new type of acid catalysts. Moreover, the C–C bond
forming reactions using a ketene silyl acetal proceeded efficiently by
the in-situ generated Tf2C=CH2.
Introduction
The organic superacidic compounds,1 such as TfOH (Tf =
CF3SO2) and Tf2NH, have been attracting considerable interest
from various fields of chemistry. For example, the acids are
utilized as catalysts in organic synthesis,2 and their conjugate
bases, as stable organic anions, represent an important structure
for ionic liquids3 and electrolytes for lithium ion secondary
batteries.4 The structurally related carbon acids depicted as
Tf2CHR are also attractive because the acidities are comparable
to that of sulfuric acid (Figure 1).5,6
However, applicable nucleophiles were still limited. One of the
most serious drawbacks was that strongly basic nucleophiles
including organometallic reagents were rapidly rendered inactive
by acids 1a and 3 existing in the reaction mixture. Application of
acid-sensitive neutral nucleophiles was also problematic.
Furthermore, in spite of a fundamental interest in the acidities of
carbon acids bearing longer perfluoroalkyl (Rf) groups,14 their
syntheses failed because of the fluorous properties of
(RfSO2)2CH2 and (RfSO2)2CHCH2CH(SO2Rf)2.
Figure 1. Structures of Triflylated Acids.
[a]
Dr. H. Yanai, R. Takahashi, Y. Takahashi, Dr. A. Kotrani, Prof. Dr.
H. Hakamata, Prof. Dr. T. Matsumoto
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: yanai@toyaku.ac.jp (HY), tmatsumo@toyaku.ac.jp (TM)
We recently developed a convenient synthetic method for 2-
Supporting information for this article is given via a link at the end of
the document.
(pyridinium-1-yl)-1,1-bis(triflyl)ethanides
4 through the three
component reaction of Tf2CH2 1a, paraformaldehyde, and
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
pyridine derivatives.15 Moreover, their unusual zwitterionic
structures were confirmed on the basis of X-ray crystallography
and computational analysis.15a Herein we report that such
pyridinium-type zwitterions provide a practical solution to the
problems with the carbon acid synthesis stated above (Eqn. 3):
The 2-fluoropyridinium congener of 4 specifically dissociated in
the solution phase,16 realizing the in-situ generation of Tf2C=CH2
2a without formation of any acidic compounds. Likewise, by using
new zwitterions 5 and 6 bearing different Rf groups (Rf = n-C4F9
and -(CF2)3-), the corresponding carbon acids and related
compounds were synthesized. This achievement presents a
general and practical way to generate highly electrophilic
(RfSO2)2C=CH2 2, which can be used as not only effective species
for installing several carbon acid functionalities but also building
blocks for fluorinated chemicals, and novel catalysts.
addition, its chemical structure was proposed only on the basis of
elemental analysis. At first, we reinvestigated the reaction
conditions and the structure of the product. As a result, we found
that by mixing 1a, paraformaldehyde, and pyridine in 1,2-
dichloroethane (DCE) at 60 °C, Koshar’s salt 4a was obtained in
quantitative yield (Eqn. 5). An X-ray crystallographic analysis of
4a was in agreement with the originally proposed structure (Figure
2), in which the planar geometry around C7 (C6–C7–S1 =
118.9°, S1–C7–S2 = 122.1°, and S2–C7–C6 = 118.6°) and
reasonable atom length between C6 and N1 (150.4(3) pm) were
key pieces of evidence.17
Results and Discussion
Synthesis of Pyridinium-type Zwitterions
Upon starting the development of the desired new reagents for in-
situ generation of (RfSO2)2C=CH2 2, we focused our attention on
2-(pyridinium-1-yl)-1,1-bis(triflyl)ethanide 4a, which was originally
reported by Koshar and co-workers in 1976 (Eqn. 4).12b They
synthesized this compound by self-promoting condensation of
Tf2CH2 1a with formaldehyde and the subsequent treatment with
a large amount of pyridine. However, owning to competitive
formation of Tf2CHCH3 (a hydrogenated product of Tf2C=CH2 2a)
in the condensation step, the overall yield was not satisfactory. In
Figure 3. Three Component Synthesis of Pyridinium-type Zwitterions.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
and N-substituted imidazoles did give the zwitterions 4j-4o,
respectively, in good to excellent yields. Under similar conditions,
bis(nonaflyl)methane 1b (Nf2CH2, Nf = n-C4F9SO2) and six-
membered cyclic derivative 1c18 were converted to the
corresponding zwitterions 5 and 6. Their zwitterion structures
were confirmed by X-ray crystallographic analysis of 4b-4o, 5a,
and 6a (see, Supporting Information).
Synthesis of Strongly Acidic Carbon Acid Derivatives
Among zwitterions derived from Tf2CH2 1a, 2-fluoropyridinium 4f
showed an interesting aspect in the temperature-variable 1H NMR
study (performed using a 0.010 M solution in CD3CN, 400 MHz).
Increasing temperature caused a significant down-field shift of the
signals of the methylene hydrogens H1 (Figure 4a).19 At the same
time, all signals of hydrogens H2-H5 on the 2-fluoropyridinium ring
were shifted up-field. Similar temperature-dependent shifts were
observed for 2-chloropyridinium 4h, whereas significantly smaller
shifts were observed in the cases of non-halogenated pyridinium
4a and 3-fluoropyridinium 4g (Figure 4b). The phenomenon
strongly suggested very rapid, probably on the order of
milliseconds, interconversion between zwitterion 4f and
Tf2C=CH2 2a/2-fluoropyridine 7 (Figure 4c) (vide infra).
Figure 2. ORTEP Drawing of Koshar’s Salt 4a. The thermal ellipsoids are
shown at 50% probability.
Our conditions for the three-component reaction were
successfully applied to the synthesis of a variety of zwitterions
(Figure 3). For example, pyridiniums 4b-4e bearing electron-
donating groups on the pyridinium ring were obtained in excellent
yields. 2-Halo- or 3-halopyridines also worked as nice reaction
components to produce pyridiniums 4f-4i. Although 2,6-
dimethylpyridine, 2,3- and 2,4-difluoropyridines did not yield the
corresponding
zwitterions,
some
nitrogen-containing
heterocycles such as quinoline, N-methylbenzimidazole, oxazole,
Figure 4. (a) Temperature dependency of 1H chemical shifts in a 0.010 mol L–1 solution of 2-fluoropyridinium 4f in CD3CN (400 MHz,  ppm). (b) Plots of chemical
shifts of the methylene hydrogens versus NMR measurement temperature (0.010 mol L–1 solutions of zwitterions 4f, 4h, 4a, and 4g in CD3CN). (c) The reversible
dissociation of 4f.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
Table 1. Carbon Acid Synthesis with Pyridinium-type Zwitterions.
Entry
4
R
Yield[a] (%)
1
4f
2-F
2-Cl
3-F
H
98 (92)
2
4h
4g
4a
4b
84 (81)
3
0
0
4
5
2-Me
<5
90
7
6[b]
7
Tf2CHCH2CHTf2 3
Tf2CH2 1a + (CH2O)n
[a] Yield on the basis of 19F NMR of crude mixture. Isolated yield is shown in
parenthesis. [b] For 3 h at room temperature. Ref. 13a
Figure 5. Synthesis of Carbon Acid Derivatives.
With 2-fluoropyridiniums on hand, we successfully
synthesized carbon acid derivatives bearing different Rf groups
(Figure 5). For example, by using 4f, 5f, and 6f, a series of carbon
acids 8b, 9, and 10 were obtained in good to excellent yields by
the reaction with naphthalen-2-ol. Likewise, anilinium-type
zwitterion 11 was formed in 92% yield from N,N-dipentylaniline. It
should be noted that the 1:2 reaction of p-cresol with 4f gave
disubstituted product 12 in 83% yield. Enolizable acetone and
enol silyl ether, derived from acetophenone, also worked as
suitable nucleophiles to give carbon acids 13a and 13b in 93%
and 79% yields, respectively.
As shown in Scheme 1, the reactions with organometallic
reagents were successful. 2-Fluoropyridiniums 4f, 5f, and 6f
smoothly reacted with both Grignard reagents and i-Bu2AlH
(DIBAL-H) to give substituted carbon acids 14-16 in good to
excellent yields. To estimate the structure-acidity relationship in
this type of carbon acid, we determined the pKa values of 14c-16c
bearing different perfluoroalkyl (or alkylene) groups in acetonitrile
by a voltammetric method.20,21 The acidity of Nf2CHCH3 15c (pKa
= 11.9) was about 100 times stronger than those of 14c (14.0)
and 16c (14.1).22 Similarly, Nf2CH2 1b (9.0) was a stronger acid
than Tf2CH2 1a (10.4) and cyclic derivative 1c (11.3). By
methylation of Tf2CH2 1a, the pKa value decreased by about 3
units. In contrast, phenylation of 1a elevated the acidity by about
3 pKa units (Tf2CHPh, 7.85).23 These data would serve as clues
for the design of stronger carbon acids directed toward superacid
catalysts.
To evaluate the performance of 2-fluoropyridinium 4f as a
reagent for the carbon acid synthesis, we examined the reaction
with p-cresol (Table 1). The reaction of 4f with 2.0 equiv of p-
cresol in acetonitrile went to completion within only 10 min at room
temperature. 1H NMR analysis of the crude material showed clean
formation of the desired carbon acid 8a and 2-fluoropyridine 7.
This result evidences that 4f smoothly produces Tf2C=CH2 2a.
The carbon acid 8a was isolated in 92% yield by bulb-to-bulb
distillation (180-200 °C at 3 mmHg) (entry 1). Although 2-
chloropyridinium 4h brought about an acceptable result under the
same conditions (entry 2), no formation of 8a was observed in the
case with 3-fluoropyridinium 4g in place of 2-fluoro derivative 4f
(entry 3). Likewise, non-halogenated and 2-methylated
pyridiniums did not show suitable reactivity (entries 4 and 5). The
use of Tf2CHCH2CHTf2 3 as a precursor of Tf2C=CH2 2a was
possible in this case, although a longer time (3 h) was required
(entry 6).13a The three-component reaction of Tf2CH2 1a,
paraformaldehyde, and p-cresol resulted in a poor conversion
because of slow formation of 2a through the self-promoting
condensation (entry 7).
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
These results indisputably demonstrated that a series of 2-
fluoropyridiniums served as the desired new reagents for in-situ
generation of (RfSO2)2C=CH2 2. Though 2-fluoropyridine
accompanies as a side product, this highly volatile compound can
be easily removed by evaporation. The low basicity also works as
an advantage to isolate the desired, strongly acidic products.24 As
shown in Figure 7, 4f and other 2-fluoropyridiniums 5f and 6f are
non-hygroscopic, crystalline compounds and they are shelf-stable
for at least several months.
Scheme 1. Reaction of 4f-6f with Organometallic Reagents.
As a good example to understand the specific reactivity of the
2-fluoropyridinium 4f, we found the unique ammonium-exchange
reaction (Figure 6). When 1.05 equiv of pyridine itself was added
to a solution of 2-fluoropyridinium 4f in acetonitrile at room
temperature, pyridinium 4a was formed quantitatively. Under
similar conditions, 4f was successfully converted to 3-
fluoropyridinium 4g in 93% yield. Although a 1:1 reaction of 4f and
2-chloropyridine yielded a mixture of 2-fluoropyridinium 4f and 2-
chloropyridinium 4h in a ratio of 1:7.0, the use of 2.0 equiv of 2-
chloropyridine was enough to realize one-sided formation of 4h
(96% yield). These data demonstrated that the thermodynamic
stability of 2-fluoropyridinium was specifically lower than other
analogues. With strongly basic 4-(dimethylamino)pyridine and
aliphatic amines such as diethylamine, quinuclidine, and 1,4-
diazabicyclo[2.2.2]octane, this reaction well proceeded and the
corresponding zwitterions 4p-4s were isolated in excellent yields.
Note that these amines never gave the zwitterions under the
Figure 7. A Picture of 2-Fluoropyridinium 4f under Air Atmosphere.
Application of 2-Fluoropyridiniums as Building Block for
Fluorinated Chemicals
To show synthetic applications of the 2-fluoropyridiniums as
building blocks for fluorinated chemicals, we next tried trapping
(RfSO2)2C=CH2
2 with 1,3-dienes via (4+2) cycloaddition.
Previously, we reported that three-component reaction of Tf2CH2
1a, paraformaldehyde, and isoprene proceeded at room
temperature to give gem-bis(triflyl)cyclohexene 17a, which was a
valuable synthetic intermediate for poly-substituted triflyl
arenes.12a In that case, a long reaction time (2.5 h) was required
(Table 2, entry 8). Although the use of Tf2CHCH2CHTf2 3 was
possible, the yield of 17a decreased with competitive
oligomerization of isoprene (entry 9).12a Note that reagent 3 itself
and Tf2CH2 1a accompanying the in-situ generation of Tf2C=CH2
2a are strongly acidic. On the other hand, 2-fluoropyridinium 4f
immediately gave 17a in 89% yield (within 10 min) without the
formation of any oligomers (entry 1). 2-Chloropyridiniums 4h also
gave comparable results (entry 2), whereas the reaction using 3-
fluoropyridinium 4g was unsatisfactory (entry 3). Moreover, the
use of non-halogenated pyridiniums 4a and 4b did not lead to
suitable production of 17a (entries 4 and 5). Likewise, 2-
fluoropyridiniums 5f and 6f derived from (RfSO2)2CH2 1b and 1c,
respectively, could be subjected to similar reaction to give
cyclohexenes 18 and 19, respectively (entries 6 and 7).
three-component
conditions
using
Tf2CH2
1a
and
paraformaldehyde, but caused neutralization of 1a giving rise to
the intermolecular salts.
Figure 6. Ammonium-exchange Reaction from 2-Fluoropyridinium 4f to Other
Ammoniums.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
Formal Catalysis by 2-Fluoropyridinium
Table 2. Trapping of In-situ Generated (RfSO2)2C=CH2 2 by isoprene.
By using 2-fluoropyridinium 4f, we achieved the carbon acid
synthesis with acid-sensitive nucleophiles and (4+2) cycloaddition
chemistry with buta-1,3-dienes including acid-sensitive 2-
(silyloxy)buta-1,3-diene. These results inspired us to attempt
formal catalysis by 2-fluoropyridinium 4f. As described above,
notably high performance of Tf2CH-based carbon acids as acid
catalysts in C-C bond forming reactions with silicon enolate
equivalents has been reported. Recently, List and co-workers
also reported an effective asymmetric carbon acid catalyst, in
which a disulfonylated, acidic C–H moiety was embedded in a
binaphthyl scaffold.25 In such carbon acid-induced Mukaiyama
aldol type reactions, it was proposed that protonation of ketene
silyl acetals by the carbon acids initially occurred to give ion pair
A (or silyl alkanide A’),26 which worked as Lewis acidic “R3Si+”
equivalents (Figure 8).27 If silyl carboxonium species B (or the
corresponding silyl alkanide B’) generated by the Michael
reaction of the Tf2C=CH2 2a with ketene silyl acetals, electrophilic
activation of carbonyl substrates would also be possible by silyl
transfer reaction from this species. Owning to the absence of any
Brønsted acids in such a reaction system, we expected a
chemoselective transformation of the carbonyl group over other
acid-sensitive functionalities in the reaction substrate.
Entry
1
4-6
4f
Rf
X
2-F
2-Cl
3-F
H
17-19
17a
17a
17a
17a
17a
18
Yield[a] (%)
CF3
89
78
2
2
4h
4g
4a
4b
5f
CF3
3
CF3
CF3
4
0
5
CF3
2-Me
2-F
2-F
0
6
n-C4F9
91
90
76
61
7
6f
-(CF2)3-
19
8[b]
9[b]
Tf2CH2 1a + (CH2O)n
Tf2CHCH2CHTf2 3
17a
17a
[a] Isolated yield. [b] For 2.5 h at room temperature. Ref. 12a.
As shown in Scheme 2, some 1,3-dienes including less
reactive ethyl sorbate smoothly reacted with 4f under mild
conditions to give the cycloadduct 17. Here it should be noted that
the reaction with 2-(silyloxy)buta-1,3-diene, which is susceptible
to hydrolysis even under slightly acidic conditions, was realized
by using 4f and cyclohexene 17d was isolated in 76% yield. One-
pot formation of the corresponding cyclohexanone 20 was also
achieved by a subsequent H3O+ workup (77% yield from 4f).
Figure 8. Generation of Catalytically Active “R3Si+” Equivalents.
With this idea in mind, we conducted the Mukaiyama aldol
reaction of 2-methylcyclohexanone 21 with a ketene silyl acetal
derived from ethyl acetate as a test case (Table 3). In our previous
work, Tf2CHCH2CHTf2 3 was found to be one of the most effective
acids (entry 1).28 -Branched acid 23 also worked as a formal
catalyst (entry 2).29 On the other hand, despite the absence of any
acidic moieties, 2-fluoropyridinium 4f efficiently promoted the
reaction (entries 3 and 4), whereas non-halogenated pyridinium
4a proved less fruitful (entry 5). These results explicitly showed
Scheme 2. Synthesis of gem-Bis(triflyl)cyclohexenes.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
Table 3. Carbon Acid- and 1,1-Bis(triflyl)alkene-induced Mukaiyama Aldol
Reaction.
Entry
Precatalyst (mol%)
Tf2CHCH2CHTf2 3 (0.05)
Tf2CHCH(Me)CH=CHPh 23 (0.25)
4f (0.5)
Yield[a] (%)
1
2
94
85
87
97
13
90
3
4[b]
5
4f (0.5)
Scheme 3. Carbonyl-selective Addition Reactions.
4f (0.5)
Dynamic Structure of Pyridinium Zwitterions in Solution
Phase
6
Tf2C=CHCH=CHPh 24 (1)
Finally, to quantify the dynamic behavior of 2-fluoropyridinium 4f
and related zwitterions, we obtained dynamic parameters from
the temperature-variable 1H NMR data (Figure 4). As mentioned
above, the NMR study demonstrated very rapid, probably on the
order of milliseconds, interconversion between zwitterion 4f and
a mixture of Tf2C=CH2 2a/2-fluoropyridine 7. Here the observed
chemical shift obs of the methylene hydrogens at each
temperature is the weighted mean of Tf2C=CH2 2a (A = 8.15 ppm)
and zwitterion 4f (B = 5.48 ppm) as illustrated in Eqn 6 (where K
= [2a]/[4f]).30 The equilibrium constant Keq can be obtained by
using the molar ratio K (Eqn. 7, where [4f]+[2a] = 0.010 mol L–1
and [2a] = [7]). We determined thermodynamic parameters rH
and rS by a van’t Hoff plot (where R = 8.314 J K–1 mol–1; Eqn 8)
and calculated the rG value (Eqn 9).
[a] Isolated yield. [b] Reaction was carried out at 0 °C.
that the thermodynamic stability of the zwitterions played a crucial
role for the formal precatalysis. As mentioned above, initial
reaction of Tf2C=CH2 2a, generated from zwitterion 4f, with
ketene silyl acetal would be a trigger for the Mukaiyama aldol
reaction. To obtain further evidence for this point, we examined
the same reaction in the presence of easily isolable 1,1-
bis(triflyl)alkadiene 2429a instead of 4f (entry 6). Although a
relatively high loading was required, the desired reaction
proceeded to give 22 in 90% yield.
As shown in Scheme 3, 2-fluoropyridinium 4f did not affect
acid-sensitive acetal moieties. For example, the reaction of ,-
dimethoxyketone 25 proceeded in a ketone-selective manner to
give the adduct 26 in 84% yield after acidic workup. Furthermore,
the addition reaction of ketene silyl acetal to less reactive lactones
27a and 27b also gave the adducts 28a and 28b in 91% and 94%
yields, respectively. Here, any side products arising from a ring-
opening reaction were not detected.
K 
1 K
A

B
(6)
(7)
 obs

[2a][7]
[4f]
0.010 K
1 K




Keq

 K


rH
T
(8)
(9)
RlnKeq  
 rS
rG  rH TrS
As shown in Figure 9, a linear relation between RlnKeq and 1/T
was obtained in the van’t Hoff plot of all four zwitterions. The
values of rH, rS and rG298 for 2-fluoropyridinium 4f were 89.6
kJ mol–1, 238 J K–1 mol–1, and 18.6 kJ mol–1, respectively.
Recently, Alcaide and Almendros have reported the rG298 of this
reaction as 18.8 kJ mol–1 by DFT computation.16a Their calculation
agrees well with our experimental data. A similar analysis was
applied to 4h, 4a, and 4g. Although the rG298 value of 2-
chloropyridinium 4h was moderate (22.6 kJ mol–1), those of
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
pyridinium 4a and 3-fluoropyridinium 4g were larger (33.4 kJ mol–
1 and 33.0 kJ mol–1, respectively).
Experimental Section
2-(2-Fluoropyridin-1-ium-1-yl)-1,1-bis((trifluoromethyl)sulfonyl)ethan-1-ide
(4f): To a solution of Tf2CH2 1a (281 mg, 1.00 mmol) in 1,2-dichloroethane
(6.0 mL), paraformaldehyde (90% purity, 69.8 mg, 2.07 mmol) and 2-
fluoropyridine (172 L, 2.00 mmol) were added at room temperature. After
being stirred for 8 h at 60 °C, the reaction mixture was concentrated under
reduced pressure. The resulting residue was washed with CHCl3 (1.0 mL
x 3) to give zwitterion 4f in 91% yield (356 mg, 0.915 mmol). The structure
was also confirmed by an X-ray crystallographic analysis. Due to its low
stability in several organic solvents, we could not detect suitable peaks in
mass spectrometry. Colorless crystals (CH3CN/hexane); Mp. 151-153 °C;
IR (ATR)  1351, 1183, 1106, 861, 776, 579 cm–1; 1H NMR (400 MHz,
CD3CN)  5.73 (2H, brs), 7.73-7.78 (1H, dd, JHH = 8.4 Hz, JHF = 4.0 Hz),
7.93 (1H, t, J = 6.8 Hz), 8.57-8.65 (1H, m), 8.92-9.01 (1H, m); 13C NMR
(100 MHz, CD3CN)  60.2, 64.5, 115.1 (d, JCF = 21.7 Hz), 121.5 (q, JCF
326 Hz), 125.3 (d, JCF = 3.7 Hz), 142.9 (d, JCF = 6.1 Hz), 147.4 (d, JCF
=
=
11.5 Hz), 159.6 (q, JCF = 279 Hz); 19F NMR (376 Hz, CD3CN)  –17.1 (6F,
s), –16.0 (1F, brs). Anal. Calcd for C9H6F7NO4S2: C, 27.77; H, 1.55; N,
3.60. Found: C, 27.49; H, 1.49; N, 3.69.
1,1-Bis((trifluoromethyl)sulfonyl)propane (14a): To
a solution of 2-
fluoropyridinium 4f (97.1 mg, 0.249 mmol) in Et2O (1.2 mL), MeMgBr (a
3.0 M solution in Et2O, 0.12 mL, 0.36 mmol) was added at 0 °C. After being
stirred for 10 min at the same temperature, the reaction mixture was
quenched with 4 M hydrochloric acid (15 mL). The resulting mixture was
extracted with Et2O (20 mL x 3) and the combined organic layer was
evaporated. Then the residue was purified by bulb-to-bulb distillation using
a Kugelrohr oven (60 °C, 5 mmHg) to give the corresponding carbon acid
14a in 91% yield (70.0 mg, 0.227 mmol). Colorless oil; IR (neat)  1462,
Figure 9. Van’t Hoff Plots of Zwitterions 4f, 4h, 4a, and 4g.
1393, 1383, 1219, 1115 cm–1 1H NMR (400 MHz, CDCl3)  1.38 (3H, t, J
;
= 7.4 Hz), 2.51-2.60 (2H, m), 4.75 (1H, t, J = 5.5 Hz); 13C NMR (100 MHz,
CDCl3)  11.9, 19.7, 78.5, 119.2 (q, JCF = 328 Hz); 19F NMR (376 MHz,
CDCl3)  –10.4 (6F, s); MS (ESI-TOF) m/z 331 [M+Na]+; HRMS calcd for
C5H6F6NaO4S2 [M+Na]+, 330.9509; found, 330.9525; Anal. Calcd for
C5H6F6O4S2: C, 19.49; H, 1.96. Found: C, 19.25; H, 1.85.
Conclusions
We have developed a concise synthetic method of pyridinium-
type zwitterions bearing highly stabilized carbanion moieties.
Among the thus obtained zwitterions, 2-halopyridiniums, in
particular 2-fluoropyridiniums, showed very interesting dynamic
behavior in the solution phase. That is, a very rapid equilibrium
between the 2-fluoropyridinium 4f and Tf2C=CH2 2a/2-
fluoropyridine 7 was fully confirmed by a temperature-variable
Ethyl 3-((tert-butyldimethylsilyl)oxy)-7-oxo-3,7-diphenylheptanoate (26):
To a solution of 5,5-dimethoxy-1,5-diphenylpentan-1-one 25 (149 mg,
0.499 mmol) and tert-butyl((1-ethoxyvinyl)oxy)dimethylsilane (122 mg,
0.601 mmol) in CH2Cl2 (1.0 mL), 2-fluoropyridinium 4f (1.9 mg, 4.9 mol)
was added at 0 °C. After being stirred for 30 min at the same temperature,
the reaction was quenched with Et3N (0.5 mL). After evaporation of the
resulting mixture, the residue was dissolved in acetone-water (1:1 v/v, 2.0
mL). This solution was treated with acetic acid (1.0 mL) for 1 h at room
temperature. The reaction was quenched with a saturated NaHCO3
aqueous solution (25 mL), extracted with EtOAc (25 mL x 3), and dried
over anhydrous MgSO4. After removal of organic solvents under reduced
pressure, the resulting residue was purified by column chromatography on
silica gel (hexane/EtOAc = 10 : 1) to give the product 26 in 84% yield (191
mg, 0.420 mmol). Colorless oil; IR (neat)  2952, 2852, 1716, 1690, 1444,
1314, 1260, 1078, 820, 778, 700 cm–1; 1H NMR (400 MHz, CDCl3)  0.05
(3H, m), 0.09 (3H, s), 0.94 (9H, s), 1.04 (3H, t, J = 7.1 Hz), 1.56-1.65 (1H,
m), 1.71-1.82 (1H, m), 2.07 (1H, ddd, J = 13.7, 11.9, 4.5 Hz), 2.25 (1H,
ddd, J = 13.7, 12.1, 4.7 Hz), 2.86 (1H, d, J = 14.3 Hz), 2.91 (2H, d, J = 7.3
Hz), 2.97 (1H, d, J = 14.3 Hz), 3.93 (2H, q, J = 7.1 Hz), 7.19-7.32 (1H, m),
7.28-7.32 (2H, m), 7.41-7.45 (4H, m), 7.52-7.56 (1H, m), 7.89-7.91 (2H,
m); 13C NMR (100 MHz, CDCl3)  –2.3, –2.2, 13.9, 18.7, 19.0, 26.1, 38.7,
41.2, 47.8, 60.1, 78.3, 125.8, 127.8, 128.0, 128.5, 132.9, 136.9, 145.1,
169.9, 199.9; MS (ESI-TOF) m/z 477 [M+Na]+; HRMS calcd for
C27H38NaO4Si [M+Na]+, 477.2437; found, 477.2440. Anal. Calcd for
C27H38O4Si: C, 71.32; H, 8.42. Found: C, 71.22; H, 8.50.
NMR study. From
a synthetic point of view, such 2-
fluoropyridiniums have several advantages as precursors of
(RfSO2)2C=CH2 2 compared to the known methods. Firstly, 2-
fluoropyridine, which is formed simultaneously with the release of
2, is a volatile and virtually non-basic compound. In the synthesis
of strongly acidic carbon acids and their derivatives, the fact that
2-fluoropyridine 7 can be easily removed by evaporation played
an important role. Secondly, no acidic species were present in this
equilibrium mixture. This led to effective reactions of
(RfSO2)2C=CH2 with acid-sensitive reagents such as
organometallic reagents and 2-silyloxydiene. Thirdly, 2-
fluoropyridiniums were successfully obtained from several
(RfSO2)2CH2 1, and such pyridiniums could be used as effective
reagents for generating (RfSO2)2C=CH2. This realized easy
access to new types of strongly acidic carbon acid derivatives.
Finally, a very fast reaction rate in the dissociation reaction of
(RfSO2)2C=CH2 (on the order of milliseconds) was one of the most
characteristic points. On the basis of this physicochemical feature,
we found that non-acidic zwitterion 4f could be used as a formal
catalyst for Mukaiyama aldol-type reactions.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
T. Ota, Y. Kawano, J. Yamashita, Y. Sakai, N. Tada, M. Ochiai, S.
Hayashi, W. Nakanishi, M. Uchiyama, J. Org. Chem. 2016, 81, 3188.
[12] a) H. Yanai, M. Fujita, T. Taguchi, Chem. Commun. 2011, 47, 7245; b)
R. J. Koshar, L. L. Barber, Jr., U.S. Patent 4 053 519, 1977.
[13] a) H. Yanai, H. Ogura, H. Fukaya, A. Kotani, F. Kusu, T. Taguchi, Chem.–
Eur. J. 2011, 17, 11747; b) H. Yanai, M. Fujita, A. Takahashi, M. Zhang,
M. Mishima, A. Kotani, T. Matsumoto, T. Taguchi, Molecules 2013, 18,
15531; c) H. Yanai, T. Yoshino, M. Fujita, H. Fukaya, A. Kotani, F. Kusu,
T. Taguchi, Angew. Chem. 2013, 125, 1600; Angew. Chem. Int. Ed. 2013,
52, 1560.
[14] Only GA of Nf2CH2 1b was reported as 288.7 kcal mol–1. See, ref. 5a.
[15] a) H. Yanai, Y. Takahashi, H. Fukaya, Y. Dobashi, T. Matsumoto, Chem.
Commun. 2013, 49, 10091; b) L. L. Barber, Jr., R. J. Koshar, U.S. Patent
3 962 346 (1976).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from the MEXT, Mitsubishi Gas Chemical Co.
Ltd., the Kurata Memorial Hitachi Science and Technology
Foundation, and the Hoansha Foundation. We thank Mr.
Haruhiko Fukaya (Tokyo University of Pharmacy and Life
Sciences, TUPLS) for the X-ray crystallographic studies, and Mr.
Yuki Yamamoto (TUPLS) for his experimental assistance. Prof.
Benito Alcaide (Universidad Complutense de Madrid) and Prof.
Pedro Almendros (Instituto de Química Orgánica General, CSIC)
are also acknowledged for helpful discussions.
[16] On the basis of our report (Ref. 15a), Alcaide and Almendros
successfully applied 2-fluoropyridinium 4f to the (2+2) and (3+2)
cycloaddition chemistry. See: a) B. Alcaide, P. Almendros, I. Fernández,
C. Lázaro, Chem. Commun. 2015, 51, 3395; b) B. Alcaide, P. Almendros,
C. Lázaro-Milla, Chem. Commun. 2015, 51, 6992; c) B. Alcaide, P.
Almendros, C. Lázaro-Milla, Chem.–Eur. J. 2016, 22, 8998.
[17] a) G. Boche, M. Marsch, K. Harms, G. K. Sheldrick, Angew. Chem. Int.
Ed. Engl. 1985, 24, 573; b) H.-J. Gais, G. Hellmann, H. Gunther, F. Lopez,
H. J. Lindner, S. Braun, Angew. Chem. Int. Ed. Engl. 1989, 28, 1025.
[18] S.-Z. Zhu, W. T. Pennington, D. D. DesMarteau, Inorg. Chem. 1995, 34,
192.
Keywords: zwitterions • Brønsted acids • acidity • homogeneous
catalyst • Lewis acids
[1]
[2]
[3]
a) Superacid Chemistry, 2nd ed. (Eds.: G. A. Olah, G. K. S. Prakash, J.
Sommer, A. Molnar), Wiley-VCH, Hoboken, 2009; b) R. N. Haszeldine,
J. M. Kidd, J. Chem. Soc. 1954, 4228; c) J. Foropoulos, Jr., D. D.
DesMarteau, Inorg. Chem. 1984, 23, 3720.
a) T. Akiyama, K. Mori, Chem. Rev. 2015, 115, 9277; b) H. Yamamoto,
D. Nakashima, in Acid Catalysis in Modern Organic Synthesis, Vol. 1
(Eds.: H. Yamamoto, K. Ishihara), Wiley-VCH, Weinheim, 2008, pp. 35–
62; c) K. Takasu Synlett 2009, 1905.
[19] In this NMR study, the methylene hydrogens were found as a broading
signal, especially at low temperature. This broading was attributed to
slow rotation of anionic C–S bonds. The rotational barrier in 4f was
determined as 53.3±0.5 kJ mol–1 at coalescence temperature (–
5.0±1.0 °C). Also see, Supporting Information.
a) Ionic Liquids in Synthesis (Eds.: P. Wasserscheid, T. Welton), Wiley-
VCH: Weinheim, 2008; b) N. V. Plechkova, K. R. Seddon, Chem. Soc.
Rev. 2008, 37, 123.
[20] K. Takamura, T. Fuse, K. Arai, F. Kusu, J. Electroanal. Chem. 1999, 468,
53.
[4]
[5]
a) K. Xu, Chem. Rev. 2014, 114, 11503; b) Xu, K. Chem. Rev. 2004, 104,
4303; c) S. S. Zhang, J. Power Sources 2006, 162, 1379.
[21] The pKa values of usual strong acids in acetonitrile (predicted from
directly measured relative acidity in DCE) were reported as follows; HCl
(10.6), HNO3 (9.4), H2SO4 (8.7), TfOH (0.7), Tf2NH (0.3). See: A. Kütt, T.
Rodima, J. Saame, E. Raamat, V. Mäemets, I. Kaljurand, I. A. Koppel, R.
Yu. Garlyauskayte, Y. L. Yagupolskii, L. M. Yagupolskii, E. Bernhardt, H.
Willner, I. Leito, J. Org. Chem. 2011, 76, 391.
The gas phase acidities GA (kcal mol–1) of Tf-substituted acids and
sulfuric acid are as follows: TfOH (299.5), Tf2NH (286.5), Tf2CH2 (300.6),
H2SO4 (302.2). See: a) I. A. Koppel, R. W. Taft, F. Anvia, S.-Z. Zhu, L.-
Q. Hu, K.-S. Sung, D. D. DesMarteau, L. M. Yagupolskii, Y. L.
Yagupolskii, N. V. Ignat’ev, N. V. Kondratenko, A. Y. Volkonskii,V. M.
Vlasov, R. Notario, P.-C. Maria, J. Am. Chem. Soc. 1994, 116, 3047; b)
I. Leito, E. Raamat, A. Kütt, J. Saame, K. Kipper, I. A. Koppel, I. Koppel,
M. Zhang, M. Mishima, L. M. Yagupolskii, R. Yu. Garlyauskayte, A. A.
Filatov, J. Phys. Chem. A 2009, 113, 8421.
[22] Although we also obtained pKa vales of 13b, 14b, and 15b in DMSO, the
pKa range was between 2.0 and 2.2. Leito and Rueping recently pointed
out that, in DMSO, pKa values of 2 or less cannot be reliably determined.
See: K. Kaupmees, N. Tolstoluzhsky, S. Raja, M. Rueping, I. Leito,
Angew. Chem. 2013, 125, 11783; Angew. Chem. Int. Ed. 2013, 52,
11569.
[6]
The pKa value of Tf2CH2 1a in DMSO was reported as 2.1. It is a stronger
Brønsted acid in solution compared with CF3CO2H (3.45). See, F. G.
Bordwell, Acc. Chem. Res. 1988, 21, 456.
[23] A. Kütt, I. Leito, I. Kaljurand, L. Sooväli, V. M. Vlasov, L. M. Yagupolskii,
I. A. Koppel, J. Org, Chem. 2006, 71, 2829.
[7]
[8]
For reviews, see: a) H. Yanai, T. Taguchi, J. Fluorine Chem. 2015, 174,
108; b) H. Yanai, Chem. Pharm. Bull. 2015, 63, 649.
[24] pKaH of 2-fluoropyridine (in H2O, 25 °C) was measured as –0.44. This
value means that 2-fluoropyridine itself is virtually a non-basic amine.
See: H. C. Brown, D. H. McDaniel, J. Am. Chem. Soc. 1955, 77, 3752.
[25] T. Gatzenmeier, M. van Gemmeren, Y. Xie, D. Höfler, M. Leutzsch, B.
List, Science 2016, 351, 949.
a) A. Takahashi, H. Yanai, T. Taguchi, Chem. Commun. 2008, 2385; b)
H. Yanai, A. Takahashi, T. Taguchi, Chem. Commun. 2010, 46, 8728; c)
H. Yanai, T. Taguchi, Chem. Commun. 2012, 48, 8967; d) H. Yanai, O.
Kobayashi, K. Takada, T. Isono, T. Satoh, T. Matsumoto, Chem.
Commun. 2016, 52, 3280.
[26] For generation of silyl methide “Tf2C(SiMe3)C6F5” by the reaction of
Tf2CHC6F5 with allyltrimethylsilane, see: A. Hasegawa, K. Ishihara, H.
Yamamoto, Angew. Chem. 2003, 115, 5909; Angew. Chem. Int. Ed.
2003, 42, 5731.
[9]
a) K. Ishihara, A. Hasegawa, H. Yamamoto, Angew. Chem. 2001, 113,
4201; Angew. Chem. Int. Ed. 2001, 40, 4077; b) K. Ishihara, A.
Hasegawa, H. Yamamoto, Synlett 2002, 1296; c) K. Ishihara, A.
Hasegawa, H. Yamamoto, Synlett 2002, 1299; d) A. Hasegawa, Y.
Naganawa, M. Fushimi, K. Ishihara, H. Yamamoto, Org. Lett. 2006, 8,
3175.
[27] a) M. Sai, M. Akakura, H. Yamamoto, Chem. Commun. 2014, 50, 15206;
b) Y. Hiraiwa, K. Ishihara, H. Yamamoto, Eur. J. Org. Chem. 2006, 1837;
c) H. Yanai, Y. Sasaki, Y. Yamamoto, T. Matsumoto, Synlett 2015, 26,
2457.
[10] D. Höfler, M. van Gemmeren, P. Wedemann, K. Kaupmees, I. Leito, M.
Leutzsch, J. Lingnau, B. List, Angew. Chem. Early View (DOI:
10.1002/ange.201609923); Angew. Chem. Int. Ed. Early View (DOI:
10.1002/anie.201609923).
[28] H. Yanai, Y. Yoshino, A. Takahashi, T. Taguchi, J. Org. Chem. 2010, 75,
5375.
[29] a) H. Yanai, S. Egawa, T. Taguchi, Tetrahedron Lett. 2013, 54, 2160; b)
H. Yanai, S. Egawa, K. Yamada, J. Ono, M. Aoki, T. Matsumoto, T.
Taguchi, Asian J. Org. Chem. 2014, 3, 556.
[11] For selected examples, see: a) R. J. Koshar, R. A. Mitsch, J. Org. Chem.
1973, 38, 3358; b) A. Hasegawa, T. Ishikawa, K. Ishihara, H. Yamamoto,
Bull. Chem. Soc. Jpn. 2005, 78, 1401; c) K. Miyamoto, S. Iwasaki, R. Doi,
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
[30] The A value was determined by a solution of Tf2CHCH2CHTf2 3 in
CD3CN (see, ref. 13b) and the B value was obtained from NMR
measurement of this solution at –40 °C.
This article is protected by copyright. All rights reserved.

10.1002/chem.201700515
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Hikaru Yanai,* Ryuta Takahashi, Yoichi
Takahashi, Akira Kotani, Hideki
Hakamata, and Takashi Matsumoto*
Page No. – Page No.
2-(Pyridinium-1-yl)-1,1-
bis((perfluoroalkyl)sulfonyl)ethan-1-
ide: a practical reagent for synthesis
of strongly acidic 1,1-
2-Fluoropyridiniums, which were prepared from (RfSO2)2CH2, paraformaldehyde, and
2-fluoropyridine, were found as shelf-stable, easy-to-handle (RfSO2)2C=CH2 sources:
by using the reaction of several nucleophiles with such reagents, superacidic carbon
acids (RfSO2)2CHR were successfully synthesized.
bis((perfluoroalkyl)sulfonyl)alkanes
This article is protected by copyright. All rights reserved.