A regioselective synthesis of poly-substituted aryl triflones through self-promoting three component reaction

Article abstract of DOI:10.1039/c1cc12093j

In the absence of any additional catalysts, the reactions of (CF ₃SO)₂CH₂, aldehydes, and 1,3-dienes gave gem-bis(triflyl)cyclohexenes in excellent yields with high regioselectivity. gem-Bis(triflyl)cyclohexene products ca

Full text of DOI:10.1039/c1cc12093j

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A regioselective synthesis of poly-substituted aryl triflones through
self-promoting three component reactionw
Hikaru Yanai, Masaya Fujita and Takeo Taguchi*
Received 12th April 2011, Accepted 11th May 2011
DOI: 10.1039/c1cc12093j
In the absence of any additional catalysts, the reactions of
(CF3SO)2CH2, aldehydes, and 1,3-dienes gave gem-bis(triflyl)-
cyclohexenes in excellent yields with high regioselectivity.
gem-Bis(triflyl)cyclohexene products can be easily converted to
the corresponding aryl trifluoromethyl sulfones.
Since the triflyl (CF3SO2, Tf) group is the strongest neutral
electron-withdrawing group,1 this functionality has been used
in several fields of chemistry.2 In organic synthesis, triflyl-
Fig. 1 In situ-generation of Tf2CQCH2 and its latent utility.
substituted acids such as TfOH and Tf2NH are widely used as
Brønsted acid catalysts or Lewis acid precursors.3 Methane
derivatives substituted by at least two Tf groups have been
also known to show the strong Brønsted acidity.4 For
example, the pKa value of Tf2CH2 in DMSO is 2.1.5 This
value means that Tf2CH2 performs as a stronger Brønsted acid
in DMSO solution compared to PhOH (18.0), PhCO2H (11.1)
and CF3CO2H (3.45). Yamamoto et al. developed homo-
geneous and heterogeneous Brønsted acid catalysts equipped
with Tf2CH groups.6 Recently, we also found that
Tf2CHCH2CHTf2 can be used as one of the most effective
Brønsted acid pre-catalysts for the Mukaiyama aldol reaction
and the Mukaiyama–Michael reaction.7 Tf2CHCH2CHTf2 2 is
easily prepared in the multi-gram scale by mixing Tf2CH2 1
and paraformaldehyde in a ratio of 2 : 1.8 In this reaction,
Tf2CHCH2CHTf2 2 is formed via self-promoting condensation
between Tf2CH2 1 and formaldehyde, and the following
Michael type addition of 1 to the resultant Tf2CQCH2
(Fig. 1). However, synthetic application of the in situ-generation
of highly electrophilic Tf2CQCH2 has not been reported.9
Therefore, we devised a three component synthesis of gem-
bis(triflyl)cyclohexenes through tandem reaction from Tf2CH2,
aldehydes and 1,3-dienes.
can be easily converted to aryl trifluoromethyl sulfones (triflones),
which are used in the molecular design of pharmaceutical
and agrochemical agents such as navitoclax and ponazuril.10
Conventional syntheses for aryl triflones include the oxidation
of aryl trifluoromethyl sulfides,11 Friedel–Crafts reaction of arenes
with Tf2O,12 substitution reactions of Tf2O with PhLi,12,13 and
trifluoromethylation of arenesulfonyl halides.14 Furthermore, a
synthetic approach via the thia-Fries rearrangement of aryl
triflates was recently reported.15 However, the practical syntheses
of poly-substituted aryl triflones have remained as a challenge in
synthetic organic chemistry. Our approach provides one of the
solutions how to synthesize these compounds.16
At first, to confirm the effective conditions for three
component synthesis of gem-bis(triflyl)cyclohexenes, we examined
the reaction of Tf2CH2 1, paraformaldehyde, and isoprene
(eqn (1)). By treating 1 with equimolar amount of paraform-
aldehyde in the presence of 2 equiv. of isoprene in acetonitrile,
the reaction completed within 2.5 h at room temperature to
give the desired gem-bis(triflyl)cyclohexene 3aa in 76% yield
without the formation of other regioisomer. In the reaction of
Tf2CHCH2CHTf2 2 with isoprene under the same conditions,
the product yield was decreased to 61% due to the competitive
polymerization of isoprene.
Herein we describe that, in the absence of any additional
catalysts, the reaction of Tf2CH2, aldehydes, and 1,3-dienes
effectively yields gem-bis(triflyl)cyclohexenes in a highly regio-
selective manner. Furthermore, the resulting cyclohexene products
School of Pharmacy, Tokyo University of Pharmacy and
Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan. E-mail: taguchi@toyaku.ac.jp; Fax: +81 676 3257;
Tel: +81 676 3257
w Electronic supplementary information (ESI) available: Details of
experiments, NMR data of all new compounds, and crystal structure
of 3af (CCDC 821320). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc12093j
ð1Þ
To reveal the scope of this three component reaction, we
examined the reactions using various 1,3-dienes. Selected results
c
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the corresponding gem-bis(triflyl)cyclohexenes 3ba, 3ca, and 3da
were obtained in excellent yields with perfect regioselectivity
in each case. Under similar conditions, synthetically useful
a-silyloxy aldehyde could be applied to this transformation
and cycloadduct 3ea was formed in 78% yield. Although the
reactivity of aromatic aldehydes was relatively low compared to
that of aliphatic aldehydes, the reaction of Tf2CH2 1, 4-nitro-
bezaldehyde, and isoprene gave product 3fa in 55% yield. In
addition, the reaction of 1, hexanal, and 2,3-dimethylbuta-1,3-
diene nicely proceeded to give the cycloadduct 3bc in 88% yield.
As an initial step for the present reaction, we consider self-
promoting condensation between Tf2CH2 1 and aldehyde
component. Thus, strongly acidic Tf2CH2 1 would act as not
only a reaction substrate but also a Brønsted acid promoter in
the reaction system. In fact, by using less acidic (PhSO2)2CH2
instead of Tf2CH2 as a reaction component, the reaction with
paraformaldehyde and isoprene resulted in no conversion of
the starting materials (eqn (2)).17 Furthermore, the addition of
a stoichiometric amount of 2,6-di-tert-butylpyridine fully
inhibited the reaction of 1, paraformaldehyde, and isoprene
for the formation of cyclohexene 3aa (eqn (3)). These facts
suggest that the strong acidity of Tf2CH2 1 plays a key role to
promote the reaction. Thus, electrophilic activation of
an aldehyde component by Tf2CH2 1 would accelerate the
dehydrative condensation step between aldehydes and 1.
The highly polarized and reactive nature of bis(triflyl)alkene
intermediates such as Tf2CQCH2 results in the rapid
Diels–Alder cycloaddition with 1,3-dienes to give cyclohexene
product 3 in a regioselective manner.
Fig. 2 Three component reaction of 1, paraformaldehyde, and
1,3-dienes.
are shown in Fig. 2. Under buta-1,3-diene atmosphere, the
stirring of Tf2CH2 1 and 1.2 equiv. of paraformaldehyde in
1,2-dichloroethane (DCE) for 6 h at 40 1C resulted in the
quantitative formation of cycloadduct 3ab. Tf2CH2 1 could be
also converted to the corresponding product 3ac in 88% yield
by treating with equimolar amount of paraformaldehyde and
2.0 equiv. of 2,3-dimethylbuta-1,3-diene at 40 1C. The reaction
with (E)-penta-1,3-diene completed after 8 h at 40 1C to give the
corresponding ortho-adduct 3ad in 81% yield as a sole product.
Likewise, penta-1,3-diene derivatives equipped with chloro
groups or ester functionality at 5-position smoothly reacted
with 1 and paraformaldehyde at 40 1C to give the ortho-adducts
3ae and 3af in excellent yields, respectively. Surprisingly, in
the reaction using ethyl sorbate as the 1,3-diene component,
gem-bis(triflyl)cyclohexene 3ag was obtained in 98% yield as a
sole product. It should be noted that a significantly high level of
the regio-control is realized in each reaction using asymmetrical
dienes such as isoprene and pentadienes. This result would be
attributed by a reactivity of a highly polarized intermediate
Tf2CQCH2. Furthermore, less reactive cyclohexadiene performed
as a nice reaction component for this reaction at 80 1C giving rise
to bicyclo[2.2.2]octene product 3ah.
ð2Þ
As shown in Fig. 3, the three component synthesis using
several aldehydes instead of paraformaldehyde was also
successfully proceeded. For example, by using aliphatic alde-
hydes such as hexanal, 3-phenylpropanal, and 3-methylbutanal,
ð3Þ
Next, to show the synthetic application of the present
three component reaction, we examined the conversion of
gem-bis(triflyl)cyclohexene products to aryl triflones via the
aromatization of the cyclohexene moiety. That is, 1,2-elimination
of triflinic acid (CF3SO2H) from gem-bis(triflyl)cyclohexene
followed by oxidation of the resulting cyclohexadiene would
provide a facile and practical approach toward poly-substituted
aryl triflones. Thermal 1,2-elimination of sulfone substrates is
an uncommon process, while Hendrickson and co-workers
have pointed out that this kind of transformation can be
achieved by thermolysis of triflones with activated b-hydrogen.18
In fact, by heating cyclohexene 3ba in degassed xylenes for 4 h at
140 1C, the thermal desulfonylation smoothly proceeded to give
cyclohexa-4,6-diene 4ba in 89% yield (Fig. 4). According to
Fig. 3 Three component reaction of 1, aldehydes, and 1,3-dienes.
7246 Chem. Commun., 2011, 47, 7245–7247
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3 (a) S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam,
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4 The gas phase acidities DGacid (kcal molꢀ1) of Tf-substituted
carbon acids are as follows: TfCH3 (339.8), Tf2CH2 (300.6), Tf3CH
(289.0). 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,
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H. Yamamoto, Synlett, 2002, 1296; (c) K. Ishihara, A. Hasegawa
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H. Yanai, M. Zhang, T. Sonoda, M. Mishima and T. Taguchi,
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T. Taguchi, Chem. Commun., 2008, 2385.
8 R. J. Koshar and L. L. Barber, Jr., U.S. Patent 4053519, 1977.
9 Due to the high electrophilicity, Tf2CQCH2 was synthesized as an
impure form, see: L. L. Barber, Jr. and R. J. Koshar, U.S. Patent
3962346, 1976.
10 (a) C. Tse, A. R. Shoemaker, J. Adickes, M. G. Anderson, J. Chen,
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31, 1219; (b) A. J. Beaumont and J. H. Clark, J. Fluorine Chem.,
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12 J. B. Hendrickson and K. W. Bair, J. Org. Chem., 1977,
42, 3875.
13 The reactions of Tf2O with aryl Grignard reagents are ineffective
for the preparation of aryl triflones, see: X. Creary, J. Org. Chem.,
1980, 45, 2727.
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16 For selected examples of the Diels–Alder approach to poly-substituted
arenes, see: (a) T. Matsumoto, T. Hosoya, M. Katsuki and K. Suzuki,
Tetrahedron Lett., 1991, 32, 6735; (b) G. Shi, S. Cottens, S. A. Shiba
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Fig. 4 Two step conversion of gem-bis(triflyl)cyclohexenes to aryl
triflones.
Corey’s procedure,19 the resulting diene 4ba was treated by
activated MnO2 at 70 1C in methylcyclohexane to give aryl
triflone 5ba in 80% yield. Likewise, 2-phenylethylated and
isobutylated cyclohexenes 3ca and 3da were smoothly converted
to the corresponding aryl triflones 5ca and 5da in excellent
yields via 4ca and 4da, respectively. During the two step
aromatization, a silyl protecting group in the reaction substrate
can be fully tolerated. Thus, thermolysis of silyloxymethyl
cyclohexene 3ea followed by MnO2 oxidation of 4ea gave aryl
triflone 5ea in good overall yield. Applying this transformation,
triflyl biaryl 5fa and tetra-substituted benzene 5bc were also
prepared in excellent yields from three component products 3fa
and 3bc. These examples clearly show that the present reaction
sequence affords a powerful tool to synthesize poly-substituted
aryl triflones in a regioselective manner.
In summary, the three component reaction of Tf2CH2 1,
aldehydes, and 1,3-dienes smoothly proceeded via self-promoting
condensation between 1 and aldehydes followed by the Diels–
Alder cycloaddition of the resulting intermediates with 1,3-dienes
and gem-bis(triflyl)cyclohexene products were obtained in good
to excellent yields. In the present reaction, Tf2CH2 1 performs
not only as a reaction component but also as a Brønsted acid
promoter for the condensation step with aldehydes. Further-
more, gem-bis(triflyl)cyclohexene products can be converted to
the corresponding aryl triflones through the stepwise aromati-
zation of cyclohexene rings. Since the three component reaction
gave gem-bis(triflyl)cyclohexenes in a highly regioselective manner,
this reaction sequence affords a facile and practical route for
poly-substituted aryl triflones. Further studies on the relation
of this chemistry are in progress in our laboratory.
Notes and references
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17 The pKa value of (PhSO2)CH2 in DMSO was reported as 12.2.
See: F. G. Bordwell, M. Van Der Puy and N. R. Vanier, J. Org.
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19 E. J. Corey and S. E. Lazerwith, J. Am. Chem. Soc., 1998, 120,
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Chem. Commun., 2011, 47, 7245–7247 7247