Synthesis, characterization, and applications of zwitterions containing a carbanion moiety

Article abstract of DOI:10.1002/anie.201208809

A trifle of triflyl: N-substituted anilines react with 1,1,3,3- tetrakis(triflyl)propane to give a 2,2-bis(triflyl)ethyl group at the para position of the ring. The product is a zwitterion with a carbanion and an ammonium moiety, and can be used as an acid catalyst for organic reactions (see scheme). Copyright

Full text of DOI:10.1002/anie.201208809

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Angewandte
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DOI: 10.1002/anie.201208809
Acids
Synthesis, Characterization, and Applications of Zwitterions
Containing a Carbanion Moiety**
Hikaru Yanai,* Tasuku Yoshino, Masaya Fujita, Haruhiko Fukaya, Akira Kotani, Fumiyo Kusu,
and Takeo Taguchi*
Carbon acids, which have active hydrogen atoms on carbon
centers, hold a unique position among organic acids. Since the
group,[6] Tf2CH-substituted compounds show excellent cata-
lyst activity compared to that of usual organic acids such as
TfOH and Tf2NH. Therefore, our synthetic methodology
realized a convenient and practical synthesis of highly active
carbon acid catalysts. Herein, we describe the reaction of
anilines with 1. On the basis of this reaction, acidic zwitterions
containing a carbanion moiety and an ammonium moiety
were successfully obtained. Furthermore, detailed structural
studies of the zwitterions and their applications are demon-
strated.
ꢀ
C H bond is so nearly homopolar, the dissociation of the
ꢀ
ꢀ
ꢀ
C H bond is less facile than those of O H and N H bonds.
Therefore, stabilization of the carbanions, which are the
conjugate bases, facilitates the ionization of the carbon acids.
For example, the bis(triflyl)methyl (Tf2CH; Tf = CF3SO2)
group is known to be acidic because of gem-disubstitution of
the carbon atom with two triflyl groups. This type of carbon
acid shows notably strong acidity both in the gas[1] and
solution phase.[2] For example, the pKa value of Tf2CH2 in
DMSO has been measured as 2.1, and this value means that
Tf2CH2 is a stronger proton donor relative to trifluoroacetic
acid (pKa in DMSO = 3.45). Recently, we developed a meth-
odology to introduce the Tf2CH group to an arene framework
using Tf2CHCH2CHTf2 (1; Scheme 1).[3] That is, the reaction
Considering our previous work,[3] we initially carried out
the
reaction
of
N,N-dimethylaniline
(4a)
with
Tf2CHCH2CHTf2 (1) in various solvents (Scheme 2). By
Scheme 2. Reactions of N,N-dimethylanilines with Tf2CHCH2CHTf2 (1).
=
Scheme 1. In situ generation of Tf2C CH2 (2).
treating 4a with an equimolar amount of 1 in acetonitrile for
3 hours at 808C, the desired product 5a was quantitatively
formed as a white precipitate in the reaction mixture. Pure 5a
was obtained in 95% yield by washing these precipitates with
chloroform. When the reaction was conducted in 1,2-
dichloroethane (DCE) under similar reaction conditions,
the reaction did not go to completion within 3 hours, but did
give 5a in 61% yield. Unfortunately, when 4-methyl-substi-
tuted N,N-dimethylaniline (4b) was treated with an equimo-
lar amount of 1 in acetonitrile the desired ortho-substituted
product was not formed.
The zwitterionic structure of 5a was confirmed by its
NMR spectra in both [D6]acetone and [D3]acetonitrile
solutions. That is, in the 1H NMR spectrum of the [D6]acetone
solution, the signal for the two hydrogen atoms on the
benzylic carbon center were observed as a singlet at d =
3.75 ppm, and any signals for hydrogen atoms on a methine
carbon center were not observed. Simultaneously, a hydrogen
on the ammonium nitrogen atom was observed as a broad
signal at d = 10.4 ppm. In addition, in the 13C NMR spectrum
of electronically rich arenes such as phenols and aryl ethers
=
with highly electrophilic Tf2C CH2 (2), which is generated by
the retro-Michael reaction of 1,[4] results in introduction of
2,2-bis(triflyl)ethyl groups to the benzene ring. As shown in
previous work by Yamamoto and co-workers[5] and our
[*] Dr. H. Yanai, T. Yoshino, M. Fujita, H. Fukaya, Dr. A. Kotani,
Prof. Dr. F. Kusu, Prof. Dr. T. Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
E-mail: yanai@toyaku.ac.jp
taguchi@toyaku.ac.jp
[**] Tf2CH2 was kindly provided by the Central Glass Co., Ltd. This work
was partially supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from the MEXT. We also thank the Asahi Glass
Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208809.
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of 5a in [D6]acetone, a signal for the anionic carbon atom was
observed at d = 65.9 ppm. Since the methine carbon atom of
3a, derived from 2,6-dimethylphenol, was observed at d =
81.0 ppm in [D6]acetone (Scheme 1), the large upfield shift of
the methine carbon atom of 5a also supported its anionic
nature. A similar observation was evident in the 1H and
13C NMR spectra of 5a in [D3]acetonitrile (see the Supporting
Information).
Furthermore, X-ray crystallographic analysis of 5a suc-
cessfully demonstrated its zwitterionic structure in the solid
phase (Figure 1). The important structural details of 5a are
listed in Table 1. Although the hydrogen atom could not be
and S2-C11 (185.0 pm).[7] This observation can be explained
by negative hyperconjugation[8] between the lone electron
pair (on C1) which occupies a p orbital (nC1) and s* orbitals of
S1-C12 and S2-C11. These nC1/s*S1-C12 and nC1/s*S2-C11 inter-
actions were also supported by the torsion angles of C2-C1-
S1-C12 (ꢀ83.58) and C2-C1-S2-C11 (ꢀ98.28). In contrast, the
ꢀ
S O bond lengths of neurtal sulfones are typically, 143.6 pm,
ꢀ
thus the somewhat longer S O bonds indicate weak deloc-
alization of nC1 into sulfonyl oxygen atoms. Interestingly, the
planar nature of C1 brings about the chirality in the molecular
structure of 5a in the solid state.[9] This crystal structure was
also constructed by a unit cell including a pair of heterochiral
two molecules of 5a (Z = 4). To the best of our knowledge, the
present crystallographic analysis is the first example of such
zwitterions containing a carbanion moiety.
Next, we carried out the reaction of several anilines with
1 in acetonitrile (Scheme 3). Under similar reaction condi-
tions, N,N-diethyl- and N,N-dipropyl-substituted anilines
Figure 1. ORTEP drawing of 5a. The thermal ellipsoids are shown at
50% probability.[16]
Table 1: Selected interatomic distances and angles in 5a.
Lengths [pm]
Angles [8]
Torsions [8]
C1-S1
C1-S2
C1-C2
S1-C12
S1-O1
S1-O2
S2-C11
S2-O3
S2-O4
N1-C6
N1-C9
N1-C10
166.6
C2-C1-S1
S1-C1-S2
S2-C1-C2
C6-N1-C9
C9-N1-C10
C10-N1-C6
120.5
120.3
119.2
114.3
110.3
110.4
C2-C1-S1-C12
C2-C1-S2-C11
C3-C2-C1-S1
C3-C2-C1-S2
C4-C3-C2-C1
C8-C3-C2-C1
C5-C6-N1-C9
C5-C6-N1-C10
ꢀ83.5
ꢀ98.2
ꢀ103.5
79.9
167.2
152.8
184.2
144.1
144.0
185.0
143.8
144.4
148.3
149.7
150.4
Scheme 3. Preperation of the zwitterions 5, which contain a carbanion
moiety.
75.9
ꢀ103.6
ꢀ35.9
89.2
were converted into the zwitterions 5c and 5d, respectively,
in good yields. Although this reaction can be applied to
aniline itself, the desired product was obtained in an impure
form. In contrast, the reaction of the secondary aniline 4e
gave the pure product 5e in 69% yield. We also found that
several N,N-disubstituted anilines form the corresponding
zwitterions in good to excellent yields. For example, the
substitution reaction of N-benzyl-N-methylaniline (4f) selec-
tively proceeded at the electronically rich benzene ring to give
the zwitterion 5 f in 95% yield. Likewise, the reactions of N-
phenylpyrolidine (4g), N-phenylpiperidine (4h), and N-
phenylmorpholine (4i), led to the isolation of the correspond-
ing zwitterions 5g–i.
located with the same degree of accuracy as the heavier
atoms, it fully supported the sp2-hybridized nature of anionic
C1 because the bond angles around C1 are 120.58 (C2-C1-S1),
120.38 (S1-C1-S2), and 119.28 (S2-C1-C2). At the same time,
the bond angles around cationic N1 (114.38 for C6-N1-C9,
110.38 for C9-N1-C10, and 110.48 for C10-N1-C6) suggested
a tetrahedral structure. It should be noted that the hydrogen
atom on N1 is found from crystallographic data. In addition,
the bond lengths of C1-S1 (166.6 pm) and C1-S2 (167.2 pm)
were significantly shorter than those of S1-C12 (184.2 pm)
The synthesized zwitterions showed somewhat weaker
Brønsted acidity compared to those of phenol-based carbon
acids such as 3. The pKa value of 3a in DMSO has been
reported as 2.3[3] and that of zwitterion 5a, derived from N,N-
dimethylaniline, was 2.4.[10] This fact suggests that the
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synthesized zwitterions make up a novel class of Brønsted
acid catalysts.[11] For instance, in the presence of catalytic
amount of the zwitterion 5d,[12] the acetal-forming reaction of
phenylpropionaldehyde with trimethyl orthoformate, which is
a typical reaction catalyzed by Brønsted acids, proceeded to
give the dimethyl acetal 6 in 95% yield [Eq. (1)]. In the
diastereoselective Mukaiyama aldol reaction of 2-methyl-
Scheme 4. Synthesis of the stabilized iminium 9.
cyclohexanone, only 1 mol% of 5d was enough to complete
this reaction and the aldol product 7 was obtained in 85%
yield in a highly diastereoselective manner [Eq. (2); TBS =
tert-butyldimethylsilyl]. Furthermore, the present zwitterion
catalysis was applied to the olefination reaction of lactone
substrates, which was recently developed by our group.[6a] The
reaction of isochroman-1-one required the use of at least
2 mol% of 3c (with three acidic carbon centers) for the
complete consumption of starting lactone.[13] In contrast, the
same reaction gave the Z-vinyl ether 8 in 79% yield by using
only 1 mol% of the zwitterion 5d instead of 3c [Eq. (3)]. This
result suggests that 5d shows higher catalyst activity than 3c,
Figure 2. ORTEP drawing of 9a. The thermal ellipsoids are shown at
50% probability.[16]
support the present iminium structure. Since torsion angles
for C7-C6-N1-C10 (ꢀ95.78) and of C5-C6-N1-C10 (85.18)
=
suggest an orthogonal relationship for the C N p plane and
the benzene plane, the resonance between the iminium
moiety and benzene moiety would not be a major factor for
the stabilization. That is, ionic bond between the iminium and
carbanion, in an intermolecular manner, as well as the
significantly low basicity of the carbanion should play crucial
roles for stabilizing this iminium species.
which bears three Tf2CH groups in the molecular structure. In
addition, it should be noted that, in contrast to deliquescent
nature of pyridinium p-toluenesulfonate,[11a] the zwitterions
including 5d did not deliquesce when open to air.
As another application for the zwitterions, we also
explored an utility of the bis(triflyl)ethanide (Tf2CꢀCH2R)
functionality as a stabilizing substituent for unstable ammo-
nium species. It is well known that iminium species derived
from ketones containing a-hydrogen atoms and secondary
amines are usually unstable and they are rapidly converted
into the corresponding enamines by tautomerizm.[14] In
contrast, we found that by stirring a solution of the zwitterion
5e in acetone at 808C, the intramolecular iminium salt 9a was
formed in 98% yield (Scheme 4). Likewise, the reaction with
cyclohexanone afforded the corresponding iminium 9b in
93% yield.
The structure of 9a was also confirmed by an X-ray
crystallographic analysis of a sample recrystallized from
acetone (Figure 2). The notably short length of the N1-C10
bond (125.4 pm) and acceptable lengths of the C10-C11 and
C10-C12 single bonds (151.8 pm and 146.2 pm, respectively)
In summary, we found that the reaction of N-alkylated
anilines with Tf2CHCH2CHTf2 (1) gives the corresponding
bis(triflyl)ethylated products in a para-selective manner. The
obtained products form a unique zwitterion structure in both
the solution and solid phase. There are few studies of
compounds containing the bis(triflyl)alkanide functional-
ity,[15] but detailed structural studies have not been reported.
The X-ray crystallographic studies of 5a and 9a discussed
herein provide useful knowledge on the structure and
behavior of the compounds. The Brønsted acidity of these
zwitterions was also sufficient to permit their use as organic
acid catalysts. For instance, the zwitterion 5d nicely catalyzed
some acid-catalyzed reactions, including an acetal-forming
reaction and a Mukaiyama-aldol-type reaction. In addition,
since the zwitterions are not deliquescent, they are a novel
and easy-to-use acid catalyst. Furthermore, the reaction of the
zwitterion 5e, derived from N-methylaniline, with ketones
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[5] a) K. Ishihara, A. Hasegawa, H. Yamamoto, Angew. Chem. 2001,
containing a-hydrogen atoms gave stable zwitterionic imi-
nium products. This result suggests that the bis-
(triflyl)alkanide functionality can be used as a stabilizing
group for usually unstable cationic species. Further studies on
this chemistry are progressing in our laboratory.
113, 4201; Angew. Chem. Int. Ed. 2001, 40, 4077; b) J. Saadi, M.
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e) A. Takahashi, H. Yanai, T. Taguchi, Chem. Commun. 2008,
2385.
[7] The bond length in neutral sulfones is typically 179 pm. See:
F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G.
Orpen, R. Taylor, J. Chem. Soc. Perkin Trans. 2 1987, S12.
[8] G. Raabe, H.-J. Gais, J. Fleischhauer, J. Am. Chem. Soc. 1996,
118, 4622.
[9] For chirality of a-sulfonyl carbanions, see: a) M. T. Reetz, S.
Hꢁtte, R. Goddard, Eur. J. Org. Chem. 1999, 2475; b) G. Boche,
M. Marsch, K. Harms, G. M. Sheldrick, Angew. Chem. 1985, 97,
577; Angew. Chem. Int. Ed. Engl. 1985, 24, 573; c) H.-J. Gais, G.
Hellmann, H. Gunther, F. Lopez, H. J. Lindner, S. Braun,
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[10] a) K. Takamura, T. Fuse, K. Arai, F. Kusu, J. Electroanal. Chem.
1999, 468, 53; b) H.-s. Kim, T. D. Chung, H. Kim, J. Electroanal.
Chem. 2001, 498, 209.
[11] For selected examples of acidic ammonium catalysts, see: a) M.
Miyashita, A. Yoshikoshi, P. A. Grieco, J. Org. Chem. 1977, 42,
3772; b) K. Wakasugi, T. Misaki, K. Yamada, Y. Tanabe,
Tetrahedron Lett. 2000, 41, 5249; c) K. Ishihara, S. Nakagawa,
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Am. Chem. Soc. 2008, 130, 16858.
[12] The dipropyl derivative 5d was adopted as a suitable acid
catalyst because of its better solubility in chlorinated hydro-
carbon solvents.
[13] In this reaction, it was also found that the carbon acid 3c shows
the higher catalyst activity compared to Tf2CHCH2CHTf2 (1),
Tf2CHC6F5, Tf2NH, and TfOH. See Ref. [6a].
Experimental Section
Preparation of 2-(4-(dimethylammonio)phenyl)-1,1-bis((trifluoro-
methyl)-sulfonyl)ethan-1-ide (5a):
N,N-dimethylaniline (4a;
45.0 mL, 0.36 mmol) was added to a solution of Tf2CHCH2CHTf2 (1;
203 mg, 0.36 mmol) in acetonitrile (0.4 mL) at room temperature.
After being stirred at 808C for 3 h, the resultant precipitates were
collected, washed with CH2Cl2 (ca. 5 mL), and dried under reduced
pressure to give the zwitterion 5a in 95% yield (140 mg, 0.34 mmol).
The structure of this compound was also confirmed by an X-ray
crystallographic analysis. Colorless crystals (acetone); Mp. 195–
~
1978C (dec.); IR (ATR): n ¼3146, 3091, 1516, 1335, 1325, 1178,
1107, 587 cmꢀ1; 1H NMR (400 MHz) in [D6]acetone: d = 3.57 (6H, s),
3.75 (2H, s), 7.61 (2H, d, J = 8.7 Hz), 7.66 (2H, d, J = 8.7 Hz),
10.4 ppm (1H, br, NH); in CD3CN: d = 3.20 (6H, s), 3.73 (2H, s), 7.44
(2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 8.82 ppm (1H, br, NH);
13C NMR (100 MHz) in [D6]acetone: d = 34.0, 48.1, 65,9 120.6, 122.5
(q, JC-F = 329.2 Hz), 131,3, 141.2, 146.7 ppm; in CD3CN: d = 33.8, 48.0,
65.6, 120.8, 122.4 (q,
JC-F = 327.9 Hz), 131.3, 140.9, 146.5 ppm;
19F NMR (376 MHz, [D6]acetone): d = ꢀ16.7 ppm (6F, s); MS (ESI-
TOF) m/z 414 [M+H]+; HRMS calcd for C12H14F6NO4S2 [M+H]+,
414.0268; found, 414.0255.
Received: November 2, 2012
Published online: December 13, 2012
Keywords: aldol reaction · carbanions · homogeneous catalysis ·
.
synthetic methodology · zwitterions
[1] The gas-phase acidities DGacid (kcalmolꢀ1) 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.
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Garlyauskayte, A. A. Filatov, J. Phys. Chem. A 2009, 113, 8421.
[2] F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456.
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Org. Chem. 2008, 73, 6448.
[15] a) L. L. Barber, Jr., R. J. Koshar, U.S. Patent 3962346, 1976; b) S.
Zhu, Q. Chen, J. Chem. Soc. Chem. Commun. 1990, 1459.
[16] CCDC 908758 (5a) and CCDC 908763 (9a) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[3] H. Yanai, H. Ogura, H. Fukaya, A. Kotani, F. Kusu, T. Taguchi,
Chem. Eur. J. 2011, 17, 11747.
[4] H. Yanai, M. Fujita, T. Taguchi, Chem. Commun. 2011, 47, 7245.
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