Reductive alkylation of bis(triflyl)methane through self-promoting formation of easily isolable 1,1-bis(triflyl)alkenes

Article abstract of DOI:10.1016/j.tetlet.2013.02.039

A convenient and practical synthesis of 1,1-bis(triflyl)alkenes via self-promoting condensation of Tf₂CH₂ and aldehydes was developed and chemical behavior of these alkenes was investigated. Among the alkenes, easily isolable 1,1-bis(triflyl)alkadienes derived from α,β-unsaturated aldehydes could be used as useful building blocks for 1,1-bis(triflyl)alkanes. The 1,1-bis(triflyl)alkane thus obtained showed catalyst activity in the acetal forming reaction, which is a typical reaction catalyzed by Br?nsted acids.

Full text of DOI:10.1016/j.tetlet.2013.02.039

Tetrahedron Letters 54 (2013) 2160–2163
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Tetrahedron Letters
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Reductive alkylation of bis(triflyl)methane through self-promoting formation
of easily isolable 1,1-bis(triflyl)alkenes
⇑
Hikaru Yanai , Saki Egawa, Takeo Taguchi
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and practical synthesis of 1,1-bis(triflyl)alkenes via self-promoting condensation of Tf2CH2
and aldehydes was developed and chemical behavior of these alkenes was investigated. Among the
Received 22 January 2013
Revised 9 February 2013
Accepted 13 February 2013
Available online 20 February 2013
alkenes, easily isolable 1,1-bis(triflyl)alkadienes derived from
a,b-unsaturated aldehydes could be used
as useful building blocks for 1,1-bis(triflyl)alkanes. The 1,1-bis(triflyl)alkane thus obtained showed cata-
lyst activity in the acetal forming reaction, which is a typical reaction catalyzed by Brønsted acids.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbon acid
C–H acidity
Triflyl group
Self-promoting reaction
Hydride reduction
Bis(triflyl)methane 1 (Tf2CH2; Tf = CF3SO2), which was first
reported in the 1950s, is known as a strong carbon acid (C–H acid).1
This compound not only performs as a superacid in the gas phase2
but also shows notably strong acidity in the solution phase. For in-
stance, its pKa value in DMSO has been reported as 2.1 indicating
the stronger acidity of this compound than that of trifluoroacetic
acid (pKa in DMSO = 3.45).3 1,1-Bis(triflyl)alkanes bearing an active
hydrogen on electronically neutral carbon atom can also be used as
strong acids. On the basis of this feature, some acid catalysts con-
taining the Tf2CH group such as Tf2CHAr,4,5 Tf2CHCH2CHTf2 2,6
and multiple carbon acids 3a–c (Scheme 1)7 have been developed.
Compared to the corresponding nitrogen acid Tf2NH and oxygen
acid TfOH, these carbon acids show an excellent catalyst
performance in several synthetic reactions including the
Mukaiyama aldol type reactions,8 the Mukaiyama–Michael reac-
tion,9 and the Friedel–Crafts acylation.4a However, synthetic meth-
odologies for organic molecules bearing the Tf2CH group are very
limited. One of the reasons for this limitation would be significantly
strong acidity of the carbon acids. That is, the strong acidity and the
high polarity of this type of carbon acids cause difficulty in both
preparation and purification steps. For example, carbanion species
derived from Tf2CH2 1 is so stabilized that its alkylation reaction
with alkyl halides does not proceed effectively.10 To overcome this
problem, we have recently reported a novel methodology to
introduce Tf2CH group(s) into several arene frameworks.7 As shown
in Scheme 1, this procedure includes nucleophilic addition of
arenes as neutral nucleophiles (H–Nu) to Tf2C@CH2, which is in
situ-generated from Tf2CHCH2CHTf2 2.11 The isolation of this alkene
was troublesome due to extremely high electrophilicity of
Tf2C@CH2 itself, although discovery of easily isolable 1,1-bis(tri-
flyl)alkenes would bring about important extensions of our
synthetic methodology. That is, 1,1-bis(triflyl)alkenes, in which
the active hydrogen in Tf2CH functionality is masked, would be
used as easy-to-handle building blocks for this type of carbon acids.
In this Letter, we describe that easily isolable 1,1-bis(triflyl)alkenes
are obtained by the reaction of a,b-unsaturated aldehydes with 1.
Furthermore, 1,1-bis(triflyl)alkenes thus obtained can be easily
converted into the corresponding carbon acids by the reaction with
NaBH4 or with CH3MgBr.
In some literatures, syntheses of 1,1-bis(triflyl)alkenes from
Tf2CH2 1 have been described.12 For example, Zhu reported that,
in acetic anhydride solvent, the reaction of benzaldehyde with 1
gives a 1,1-bis(triflyl)alkene.12a However, it was also mentioned
that this alkene is highly sensitive to moisture and under open
air condition it rapidly decomposes to the starting aldehyde and
1. We also observed that the reaction of benzaldehyde with 1 in
1,2-dichloroethane (DCE) at room temperature gives the corre-
sponding alkene in only 7% yield (Eq. 1). These facts suggest that
the rate of hydrolysis of the alkene is significantly faster than that
of the condensation reaction. That is, the 1,1-bis(triflyl)alkenes
derived from aromatic aldehydes such as benzaldehyde are kinet-
ically and thermodynamically unstable species in the presence of
equimolar amount of water. To improve the low stability of this
type of alkenes, we devised the use of sterically less hindered
⇑
Corresponding author. Tel.: +81 426 76 3265; fax: +81 426 76 3257.
E-mail address: yanai@toyaku.ac.jp (H. Yanai).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.039

H. Yanai et al. / Tetrahedron Letters 54 (2013) 2160–2163
2161
self-promoting
condensation
Tf
Tf
H
O
DCE, rt, 3-10 h;
method A or B
1
Tf2CH2
H
Tf2C CH2
Tf2CHCH2CHTf2
Tf2CH2
(CH2O)n
1
2
Ar
Ar
Tf
Tf
H Nu
4 (1.0-1.2 equiv)
1
5
H
C
Nu
Tf
Tf
H
Tf
Tf
H
Tf
Tf
H
3
Tf HC
2
Tf HC
2
F
O
O
HO
OH
CHTf
OH
CHTf
X
F
CO2t-Bu
5j 82% (A)
Br
5i 95% (A)
2
H C
3
CH
3
2
t-Bu
5b (X = 4-CH3) 95% (A)
5c (X = 4-OCH3) 95% (B)
5d (X = 3-OEt) 96% (A)
Tf HC
CHTf
2
2
Tf HC
2
OH
3b
Scheme 1.
3c
3a
Tf
Tf
H
Tf
Tf
5e (X = 4-Cl)
5f (X = 4-Br)
5g (X = 2-Br)
97% (A)
92% (A)
94% (A)
H
a
,b-unsaturated aldehydes as a reaction substrate. In this case, the
O
5h (X = 4-NO2) 95% (A)
CO2CH3
5k 78% (B)
desired 1,1-bis(triflyl)alkadienes would show a higher stability to
moisture since the rate of nucleophilic addition reaction of Tf2CH2
1 to aldehydes would be faster, at the same time, thermodynamic
stability of the alkadiene would be improved. Keeping this idea in
our mind, we examined the reaction of cinnamaldehyde 4a with 1.
This reaction was smoothly completed for 5 h at room temperature
to give the corresponding 1,1-bis(triflyl)alkadiene 5a in 95% yield
(Eq. 2). The reaction mixture could be purified by simple washing
with hexane (method A) or by column chromatography on neutral
silica gel (method B). In this reaction, acidic additives were not
needed and Tf2CH2 1 performed not only as a reaction substrate
but also as a Brønsted acid promoter.13 In addition, it should be
noted that the isolated alkadiene 5a is so stable crystalline com-
pound under air atmosphere (Fig. 1).
5m 97% (A)
Figure 2. Self-promoting condensation reaction of Tf2CH2 1 with
a,b-unsaturated
aldehydes.
it should be noted that some acid-sensitive groups such as tert-
butoxycarbonyl group and ,b-unsaturated ester functionality
a
were well tolerated. Furthermore, furan-bearing 1,1-bis(triflyl)
alkadiene 5m can be obtained in 97% yield. In most cases, accept-
ably pure 5 was isolated by washing the reaction mixture with
hexane (method A). If necessary, chromatographic purification
using neutral silica gel (method B) was successfully applied.
Interestingly, aliphatic aldehyde such as hexanal reacted with
Tf2CH2 1 under similar conditions to give a mixture of
rated sulfone 5n and b, -unsaturated sulfone 6n (5n/6n = 1:2.0) in
71% yield (Eq. 3). By monitoring of this reaction using a NMR
spectrometer, it was defined that ,b-unsaturated sulfone 5n is a
primary product of the reaction and it is converted into b, -unsat-
a,b-unsatu-
c
On the basis of this finding, we examined the reactions of
Tf2CH2 1 with several
a
,b-unsaturated aldehydes.14 As shown in
a
Figure 2, several cinnamaldehyde derivatives performed as suit-
able substrates for this reaction. For example, the reactions of
methylated and alkoxylated cinnamaldehydes 4b–4d with 1 gave
the corresponding alkadienes 5b–5d in excellent yields. Under
the same conditions, cinnamaldehydes 4e–4g and 4i containing
halogen atom(s) on the benzene ring were also converted into
the corresponding products 5e–5g and 5i. Likewise, the reaction
of nitrocinnamaldehyde 4h afforded 1,1-bis(triflyl)alkadiene 5h
in 95% yield. Since this reaction proceeds under mild conditions,
c
urated sulfone 6n in the reaction system (for details, see: Supple-
mentary data). That is, isomerization reaction of 5n catalyzed by
unreacted Tf2CH2 1 reversibly afforded relatively stable 6n. Similar
tendency was observed in the reaction of isovarelaldehyde 4o
(Eq. 4). In this case, a mixture of
b, -unsaturated sulfone 6o was obtained in 81% yield in a ratio
of 1:2.0. On the other hand, phenylacetaldehyde 4p gave b, -unsat-
a,b-unsaturated sulfone 5o and
c
c
urated sulfone 6p, which is stabilized by the resonance effect, in a
selective manner.
Tf
Tf
H
Tf2CH2
1
O
Tf
Tf
H
O
(1)
(2)
CHTf2
α
Tf2CH2
DCE, rt, 7 h;
1
DCE, rt, 5 h
Ph
H
β
Ph
H
(1.05 equiv)
7%
(3)
(4)
bulb-to-bulb dist.
Tf
Tf
O
H
Tf2CH2
1
H3C
5n
6n
H3C
H3C
H
4n (1.0 equiv)
71% (5n/6n = 1 : 2.0)
DCE, rt, 5 h
Ph
Ph
5a 95%
Tf
Tf
Tf2CH2
DCE, rt, 2.5 h;
1
O
CHTf2
4a (1.05 equiv)
H
H
purification
R
R
R
(1.5 equiv)
5
6
4o (R = i-Pr) bulb-to-bulb dist. 81% (5o/6o = 1 : 2.0)
4p (R = Ph) method A 80% (6p only)
From these results, we noticed a similarity of the reaction pat-
tern between Tf2CH2 1 and secondary amines in the reaction with
aldehydes. That is, secondary amines react with
a,b-unsaturated
Figure 1. Compound 5a under air atmosphere.

2162
H. Yanai et al. / Tetrahedron Letters 54 (2013) 2160–2163
aldehydes to give the corresponding iminiums and the reaction
with aliphatic aldehydes containing -hydrogen(s) results in the
Tf
Tf
H
CHTf2
H
CHTf2
1) NaBH4 (2.0 equiv)
EtOAc, -78 °C, 1 h;
a
formation of enamines. In general, the reductive alkylation
reaction of secondary amines via hydride reduction of in situ-gen-
erated iminium species is one of the most promising approaches to
tertiary amines. Therefore, we examined 1,4-reduction of isolated
1,1-bis(triflyl)alkadiene 5. After screening of easily available reduc-
ing agents, we adopted NaBH4 as the most effective reagent (Fig. 3).
That is, when a solution of 5a derived from cinnamaldehyde 4a and
Tf2CH2 1 in EtOAc was treated by 2.0 equiv of NaBH4 at À78 °C, 5a
was completely consumed within 20 min.15 After quenching with
4 M hydrochloric acid, the desired carbon acid 7a was isolated in
80% yield by bulb-to-bulb distillation of the reaction mixture using
a Kugelrohr oven. In this case, undesired 1,6-reduction products
were not isolated. Likewise, DIBAL-H was an effective reducing
agent. For instance, the reaction of 5a with 1.1 equiv of DIBAL-H
in CH2Cl2 for 4 h at room temperature gave 7a in 87% yield (see,
Supplementary data). Under the optimized conditions using mild
NaBH4, 1,1-bis(triflyl)alkadienes 5b–5m containing electron-
donating groups and electron-withdrawing groups on the benzene
ring gave the corresponding carbon acids 7b–7m in good to excel-
lent yields. In particular, it should be noted that halogens, nitro
group, and ester functionality were not impaired under the present
2) 4 M HCl
3) bulb-to-bulb dist.
H3C
H3C
H3C
6n
5n
7n 75%
(5n/6n = 1 : 2.0)
Tf
Tf
CHTf2
CH3
1) CH3MgBr (1.5 equiv)
Et2O, -78 °C, 1 h;
H
2) 4 M HCl
Ph
Ph
3) bulb-to-bulb dist.
8 73%
5a
Scheme 2.
(triflyl)alkenes giving rise to the corresponding 1,1-bis
(triflyl)alkanes. The present methodology in a two step manner
would be a powerful method to synthesize strongly acidic carbon
acids. Since Tf2CH-substituted compounds have been reported as
one of the most effective acid catalysts in several reactions, the
present work would realize the development of novel Brønsted
acid catalysts.16 Further studies on this methodology are in pro-
gress in our laboratory.
NaBH4 reduction conditions. In the case of
a,b-unsaturated ester
5k, the reaction cleanly afforded carbon acid 7k (88% yield by
NMR analysis). However, due to its high boiling point, the isolated
yield of 7k was moderate.
Acknowledgments
As shown in Scheme 2, we also found that not only
a,b-unsatu-
We thank Dr. Arata Takahashi (Central Glass Co., Ltd.) for help-
ful discussion. This work was partially supported by a Grant-in-Aid
for Scientific Research on Innovative Areas ‘Advanced Molecular
Transformations by Organocatalysts’ from MEXT. We also thank
the Asahi Glass Foundation.
rated sulfone 5 but also b, -unsaturated sulfone 6 can be converted
c
into the corresponding carbon acid 7 by the NaBH4 reduction. For
instance, a mixture of 5n and 6n in a ratio of 1:2.0 was treated with
NaBH4 at À78 °C to give carbon acid 7n in 75% yield after bulb-to-
bulb distillation. Furthermore, the reaction of 5a with CH3MgBr in
Et2O provided methylated carbon acid 8 in 73% yield. This finding
suggests that chiral carbon acids can be synthesized by alkylation
of 1,1-bis(triflyl)alkadienes, in principle.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.039.
In summary, we found that the self-promoting reaction of
Tf2CH2 1 with
a,b-unsaturated aldehydes gives easily isolable
1,1-bis(triflyl)alkadienes in excellent yields. It should be noted that
additives were not needed for smooth reaction. When this reaction
could be applied to aliphatic aldehydes, unusual b,c-unsaturated
References and notes
sulfones were formed as the major products. In addition, we devel-
oped hydride reduction and methylation reaction of the 1,1-bis
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Gacid values (kcal molÀ1) of some strong acids are as follows: H2SO4 = 302.2,
D
Gacid of Tf2CH2 1 has been reported as 300.6 kcal molÀ1. The
D
TfOH = 299.5, Tf2NH = 286.5 (a) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.-Z.;
Hu, L.-Q.; Sung, K.-S.; DesMarteau, D. D.; Yagupolskii, L. M.; Yagupolskii, Y. L.;
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O O O O1
Tf
H
S
S
1) NaBH4 (2.0 equiv)
EtOAc, -78 °C, 1-3 h;
Tf
C
F3C
CF3
4
H
H
H
2) 4 M HCl
3) bulb-to-bulb dist.
6
3. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
Ar
Ar
5
7
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CHTf2
CHTf2
CHTf2
F
X
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R. J.; Barber, L. L., Jr. U.S. Patent 4,053,519, 1977.
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Br
CO2CH3
7k 55%
CHTf2
7a (X = H)
80%
7i 80%
7b (X = 4-CH3) 95%
7d (X = 3-OEt) 94%
7e (X = 4-Cl)
7f (X = 4-Br)
7g (X = 2-Br)
88%
72%
96%
O
7m 71%
7h (X = 4-NO2) 91%
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Figure 3. NaBH4 reduction of 1,1-bis(triflyl)alkadiene 5.

H. Yanai et al. / Tetrahedron Letters 54 (2013) 2160–2163
2163
12. (a) Zhu, S.-Z. Synthesis 1994, 261; (b) Hanack, M.; Hackenberg, J.; Menke, O.;
Subramanian, L. R.; Schlichenmaier, R. Synthesis 1994, 249; (c) Koshar, R. J.;
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13. In fact, the reaction in the presence of equimolar amount of 2,6-di-tert-
butylpyridine, which works as a sterically hindered base, resulted in notably
slow conversion of starting materials and 1,1-bis(triflyl)alkadiene 5a was
obtained in 16% yield by the reaction for 10 h Hollis, T. K.; Bosnich, B. J. Am.
Chem. Soc. 1995, 117, 4570.
15. When usual alcoholic solvents such as EtOH and CH3OH instead of EtOAc were
used, the reaction was not completed.
16. We confirmed that carbon acid 7a works as a Brønsted acid catalyst. For
example, in the presence of 4 mol % of 7a, 3-phenylpropionaldehyde was
converted into the corresponding dimethyl acetal in 95% yield by the reaction
with trimethyl orthoformate. Also see, Supplementary data.
14. Under similar conditions, the self-promoting condensation reaction of
a,b-
unsaturated ketones such as benzylideneacetone with Tf2CH2
proceed.
1 did not