Stereoselective synthesis of vinyl triflones and heteroaryl triflones through anionic O→Cvinyl and N→Cvinyl trifluoromethanesulfonyl migration reactions

Article abstract of DOI:10.1002/anie.201307535

Six transformations, one pot: Various di- and trisubstituted vinyl triflones, as well as several heteroaryl triflones, were stereoselectively synthesized from easily accessible gem-dibromovinyl substrates (see scheme, Boc=tert-butoxycarbonyl). The highlig

Full text of DOI:10.1002/anie.201307535

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DOI: 10.1002/anie.201307535
Synthetic Methods
Stereoselective Synthesis of Vinyl Triflones and Heteroaryl Triflones
through Anionic O!Cvinyl and N!Cvinyl Trifluoromethanesulfonyl
Migration Reactions**
Xiu-Hua Xu, Misaki Taniguchi, Xin Wang, Etsuko Tokunaga, Tomohiro Ozawa,
Hideki Masuda, and Norio Shibata*
Vinyl triflone (trifluoromethanesulfone) is a simple, unique,
and useful structural unit which takes advantage of the strong
electron-withdrawing power[1] and the manifold reactivity[2] of
the triflyl (trifluoromethanesulfonyl; SO2CF3) group.
Research on vinyl triflone began about two decades ago.[3]
Although vinyl triflones have some potential with applica-
tions in medicinal chemistry and material science, they are not
widely available.[4] There are mainly two methods to synthe-
size vinyl triflones: direct condensation of triflyl-containing
building blocks with aldehydes[4f,5] and indirect transforma-
tion from alkynyl triflones[6] or alkyl triflones.[3a,4d,7] Although
these methods are efficient, they suffer from either compa-
rably narrow substrate scope or multiple reaction steps.
Critically, they require precursors which already contain
Figure 1. Strategies for substituted vinyl triflones: a building block
ꢀ
method and a direct method (Cvinyl Striflyl bond formation).
Oaryl!Cvinyl sulfonyl migration reaction is still a challenge. As
in these remote anionic Fries-type rearrangement reac-
tions,[13] the chemo-, regio-, and stereoselectivity must be
simultaneously considered. Thus, to date, only few examples
have been reported, and the substrates were limited to
a special structure.[14] In continuation of our recent research
interest in triflone chemistry,[12,15] we report herein our
original results about stereoselective synthesis of substituted
vinyl triflones from easily accessible gem-bromovinyl sub-
strates through an anionic thia-Fries-type rearrangement. A
ꢀ
a carbon–triflyl moiety, that is, C SO2CF3. To meet the
increasing demand of organofluorine compounds in agro-
chemicals, pharmaceuticals, and materials,[8] it is highly
desirable to develop straightforward methods for the syn-
ꢀ
thesis of vinyl triflones by direct Cvinyl Striflyl bond formation
(Figure 1).
ꢀ
The anionic Fries rearrangement, developed in the
1980s,[9] has become a common concept in the synthesis of
polysubstituted aromatics.[10] The anionic thia-Fries rear-
rangement, uncovered by Lloyd-Jones in 2003, has been
widely applied in the synthesis of various aryl triflones.[11]
Recently, our group reported the regioselective synthesis of
various heteroaryl triflones by anionic thia-Fries rearrange-
ment.[12] Next we were wondering if we could extend its
application to the synthesis of vinyl triflones. However, the
Cvinyl Striflyl bond formation was realized with the help of an
intramolecular migration reaction.
The reaction of gem-dibromovinyl substrates with nBuLi
(2.0 equiv) is well known as the general method for preparing
alkynes [Eq. (1), Scheme 1].[16] We were pleased to find that
[*] Dr. X.-H. Xu, M. Taniguchi, X. Wang, E. Tokunaga,
Prof. Dr. T. Ozawa, Prof. Dr. H. Masuda, Prof. Dr. N. Shibata
Department of Frontier Materials&Department of Nanopharma-
ceutical Science, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
Scheme 1. Reactions of gem-dibromovinylbenzenes with nBuLi. Gen-
eral method for alkynes [Eq. (1)] and our new method for vinyl triflone
[Eq. (2)]. Yield was determined by 19F NMR spectroscopy using
trifluoromethoxybenzene as an internal standard. THF=tetrahydro-
furan.
[**] This study was financially supported in part by the Platform for Drug
Discovery, Informatics, and Structural Life Science from the Ministry
of Education, Culture, Sports, Science and Technology (Japan), by
Grants-in-Aid for Scientific Research from MEXT (Ministry of
Education, Culture, Sports, Science and Technology) (24105513,
Project No. 2304: Advanced Molecular Transformation by Organo-
catalysts), and JST (ACT-C: Creation of Advanced Catalytic Trans-
formation for the Sustainable Manufacturing at Low Energy, Low
Environmental Load). X.H.X. thanks JSPS Postdoctoral Fellowship
Program for Foreign Researchers. T.O. and H.M. conducted X-ray
crystallographic analysis of 5a.
the situation was totally different for our designed compound
1a, having an ortho OTf substituent. The O!Cvinyl triflyl
migration reaction proceeded, thus giving the E-vinyl triflone
2a, in 91% yield, stereoselectively [Eq. (2), Scheme 1].
Interestingly, the amount of base is critical. When 1.0 equiv-
alent of nBuLi was added, about half of 1a was converted and
the desired product 2a was obtained in low yield (22%). The
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307535.
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reaction conditions, including base, solvent, and temperature,
were further screened, but no better result was obtained (see
Table S1 in the Supporting Information). It should be noted
that the triflyl group plays an important role in ensuring that
the migration process takes place in this intramolecular
rearrangement reaction. Starting from compounds 1a’ or 1a’’,
the respective methanesulfonyl or carbamoyl migration
reactions could not be detected at all.
The scope of this anionic O!Cvinyl triflyl migration was
then investigated with various ortho-gem-dibromovinyl-
phenyl triflates (1). The results are summarized in
Scheme 2. All the triflates 1b–h, bearing either electron-
Scheme 3. Extension of intramolecular migration reactions. Boc=tert-
butoxycarbonyl.
of trisubstituted vinyl triflones. Recently, the tandem reac-
tions of gem-dibromovinyl systems have been widely applied
in the synthesis of bifunctionalized compounds.[18] Influenced
by this concept,
a one-pot procedure was designed
(Scheme 4). Different electrophiles were added to the
Scheme 2. Stereoselective synthesis of vinyl triflones. Reactions of
ortho-gem-dibromovinyl phenyl triflates 1 with nBuLi. Yields are of the
isolated products.
Scheme 4. Stereoselective synthesis of substituted vinyl triflones.
Tandem reactions by treatment of 1a with nBuLi and subsequent
reaction with different electrophiles. MOM=methoxymethyl.
donating or electron-withdrawing substituents in different
positions, underwent remote triflyl migration to give the
corresponding vinyl triflones 2b–h in moderate to good yields.
In the case of the naphthyl triflate 1i, although the reaction
mixture was a bit complex, the desired compound 2i was
obtained in acceptable yield. Based on all of the olefinic 1H–
1H coupling constants (15.0–15.6 Hz) in the 1H NMR spectra,
the products 2a–i were assigned as E isomers.[17]
Fortunately, this O!Cvinyl triflyl migration strategy was
successfully extended to three types of reactions (Scheme 3).
First, not only the triflyl group, but also the nonaflyl
(nonafluorobutanesulfonyl) group could undergo this migra-
tion process. Under the same reaction conditions, the com-
pound 3a was converted into the vinyl nonaflone 4a in 77%
yield [Eq. (3), Scheme 3]. Second, the N!Cvinyl triflyl migra-
tion in compound 3b also proceeded well, thus giving a new
type of vinyl triflone, 4b, in 64% yield [Eq. (4), Scheme 3].
The last extension was a 1,6-triflyl migration. Starting from
the indole derivative 3c, the vinyl triflone 4c was obtained in
52% yield [Eq. (5), Scheme 3]. To the best of our knowledge,
this is the first example of anionic 1,6-migration reaction.
After obtaining the above disubstituted vinyl triflones, the
reaction conditions were further optimized for the synthesis
reaction mixture after the addition of nBuLi. When the
electrophiles were MeI, MeSSMe, and PhCHO, the corre-
sponding trisubstituted vinyl triflones 5a–c were obtained in
moderate to good yields with excellent stereoselectivities. A
one-pot, three-step reaction was also developed, wherein
nBuLi, MeI, and MOMCl, were added sequentially to the
reaction mixture of 1a. After column chromatography the
protected trisubstituted vinyl triflone 5d was obtained in 73%
yield. The structure of the compounds 5 was confirmed by X-
ray crystallographic analysis of 5a.[19]
We were next interested in the synthesis of heteroaryl
triflones from a biological point of view.[15] In this tandem
reaction system, when the electrophile was HCO2Me, intra-
molecular cyclization happened after the rearrangement/
substitution steps (Scheme 5). The biologically attractive
heteroaryl triflones, 3-triflyl- and 3-nonaflyl-2-hydroxy-2H-
chromenes (6a–e), were obtained in good yields. Different
functional groups, such as methyl, methoxy, and phenyl, were
all well tolerated.
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These facts can be explained by the strong electron-with-
drawing power of the triflyl group in B, because it activates
the reactivity of Br more towards nBuLi than the reactivity of
Br in 1. The intermediate C, which formed rapidly, isomerized
to generate the more thermodynamically stable intermediate
C’.[20] This in situ isomerization led to the stereoselective
formation of the final products 2 and 4–7, which were
obtained from the subsequent reaction with different electro-
philes. It is noteworthy that the strong electron-withdrawing
power of the triflyl group stabilized the adjacent carbanion in
C’. Above all, six transformations are involved in this reaction
system: lithium–bromine exchange, 1,5-triflyl migration,
lithium–bromine exchange, Z to E isomerization, and reac-
tions of a carbanion or phenolate oxygen atom with electro-
philes. Although the intermediate D can also be produced by
competing a-elimination reactions from A, the migration
process from A to B should be predominant since the strong
electron-withdrawing trifluoromethyl[1b] substituent of the
sulfonyl group remarkably enhances its electrophilic reac-
tivity.
Scheme 5. Synthesis of heteroaryl triflones 6 by a rearrangement/sub-
stitution/cyclization reaction sequence.
Another type of heteroaryl triflone, the coumarin deriv-
ative 7, was also synthesized in the one-pot rearrangement/
substitution reaction with oxalyl chloride as the electrophile
(Scheme 6). The formation of 7 may be explained by an
additional intramolecular cyclization step.[5d]
In conclusion, we have developed a new approach for the
stereoselective synthesis of various vinyl triflones. Starting
from gem-dibromovinyl substrates, several types of disubsti-
tuted vinyl triflones were conveniently obtained by remote
O!Cvinyl/N!Cvinyl triflyl migration reactions. Different tri-
substituted vinyl triflones, including two types of novel
heteroaryl triflones, were also synthesized by a one-pot
rearrangement/substitution sequence. Further studies to
expand the substrate scope and to develop applications are
in progress.
Scheme 6. Synthesis of coumarin triflone 7 by a tandem reaction.
According to the above results, a mechanism for these
rearrangement reactions is proposed in Scheme 7. When
1 reacted first with nBuLi, the common lithium–bromine
exchange gave the intermediate A, which then underwent
triflyl migration to afford B. The intermediate B then was
converted into C by a second lithium–bromine exchange
reaction. The second lithium–bromine exchange reaction
should be faster than that of the first nBuLi reaction since
1) 2 equivalents of nBuLi are required for complete conver-
sion, and 2) a trace amount of the brominated vinyl triflone 8
was detected even when 1 equivalent of nBuLi was used.
Received: August 27, 2013
Published online: October 15, 2013
Keywords: alkenes · lithiation · rearrangement ·
.
stereoselectivity · synthetic methods
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