A novel synthesis of functionalized 1,1-difluoro-1-alkenes via isolable 2,2-difluorovinylsilanes

Article abstract of DOI:10.1016/S0040-4039(02)02652-7

Various 1,1-difluoro-1-alkenes such as monosubstituted 1,1-difluoro-1-alkenes, 2-bromo-1,1-difluoro-1-alkenes, and 1,1-difluoro-3-hydroxy-1-alkenes are prepared in two simple steps from 1-trifluoromethylvinylsilane: (i) its S_N2′ reaction with nucleophiles to construct 2,2-difluorovinylsilanes and (ii) the subsequent substitution of electrophiles for the vinylic silyl group.

Full text of DOI:10.1016/S0040-4039(02)02652-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 707–710
A novel synthesis of functionalized 1,1-difluoro-1-alkenes via
isolable 2,2-difluorovinylsilanes
Junji Ichikawa,* Yuichiro Ishibashi and Hiroki Fukui
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 1 November 2002; revised 16 November 2002; accepted 22 November 2002
Abstract—Various 1,1-difluoro-1-alkenes such as monosubstituted 1,1-difluoro-1-alkenes, 2-bromo-1,1-difluoro-1-alkenes, and
1,1-difluoro-3-hydroxy-1-alkenes are prepared in two simple steps from 1-trifluoromethylvinylsilane: (i) its SN2% reaction with
nucleophiles to construct 2,2-difluorovinylsilanes and (ii) the subsequent substitution of electrophiles for the vinylic silyl group.
© 2003 Elsevier Science Ltd. All rights reserved.
Among fluorine-containing molecules, 1,1-difluoro-1-
alkenes are of special interest, due to their diverse
utility as building blocks for fluorinated compounds
and polymers.1 The activity of these compounds as new
types of enzyme inhibitors has also attracted much
attention in recent years.2 Although a number of exam-
ples of the preparation of 1,1-difluoro-1-alkenes have
been reported,1–3 the generality of these methods are
limited. The development of general synthetic methods
for highly functionalized 1,1-difluoro-1-alkenes still
remains a challenge of practical importance.
For the synthesis of diverse 1,1-difluoro-1-alkenes, it is
necessary to prepare a variety of 2,2-difluorovinyl-
silanes. Since the carbon substituents at the 1-position
of reported 2,2-difluorovinylsilanes are limited to
phenyl and triphenylsilylmethyl groups,8 our investiga-
tion started with the development of a widely applica-
ble synthetic route to these compounds.
3,3,3-Trifluoropropene derivatives react with nucle-
ophiles in an SN2% fashion to afford 1,1-difluoro-1-alke-
nes.9 The following limitations of this reaction,
however, have restricted its applicability: the necessity
of (i) an electron-withdrawing group such as a carbonyl
or phenyl group on the 2-position of the trifluoro-
propene framework and/or (ii) highly reactive nucle-
ophiles such as alkyllithiums. We expected that these
drawbacks could be overcome by utilizing the a-anion-
stabilizing effect of silicon to support the generation of
intermediary anion 2 and therefore to promote the SN2%
reaction.10 The resulting vinylsilanes 3 would allow in
turn the introduction of the second substituent by the
One straightforward route to their synthesis involves
the generation and reaction of 2,2-difluorovinyl-
metals.3–5 However, very few 2,2-difluorovinylmetals
lacking an a-anion-stabilizing group at the 1-position
have been described,3,6 due to the propensity of 2,2-
difluorovinylmetals to undergo b-elimination of a metal
fluoride leading to 1-fluoro-1-alkynes.4,7 As a solution
to this problem, we have already developed thermo-
stable 2,2-difluorovinylboron and -zirconium species to
achieve the difluoroalkene synthesis via transmetalation
to copper and zinc intermediates.3,6 The corresponding
silicon species also attracted our attention. We wish to
report herein a novel synthesis of 1,1-difluoro-1-alkenes
via 2,2-difluorovinylsilanes, which are quite ther-
mostable, easy to handle and can be stored under air.
Keywords: alkenes; fluorine and compounds; silicon and compounds;
substitution.
* Corresponding author. Tel./fax: +81-3-5841-4345; e-mail:
junji@chem.s.u-tokyo.ac.jp
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02652-7

708
J. Ichikawa et al. / Tetrahedron Letters 44 (2003) 707–710
Table 1. SN2% reaction of 5 with nucleophiles
replacement of the silyl group. Thus, as depicted in
Scheme 1, the sequence of reactions starting from 1-
trifluoromethylvinylsilane 1 could provide a wide vari-
ety of 1,1-difluoro-1-alkenes 4 bearing two kinds of
substituents (Nu, E).
Taking into consideration its boiling point and SN2%
reactivity,11 we adopted dimethylphenylsilyl group for
1. After some attempts, we found that the in situ
generated 1-trifluoromethylvinylmagnesium bromide12
was efficiently trapped with dimethylphenylsilyl chlo-
ride to afford 5 in 80% yield (Scheme 2).13 Vinylsilane 5
thus obtained was stable enough to be stored at room
temperature under air for long periods (no less than 6
months), despite a report on the susceptibility to b-
elimination generating 1,1-difluoroallene.14
We then investigated the SN2% reaction of 5 with various
nucleophiles. The results are summarized in Table 1.
SN2% Products 6 were obtained in excellent yield for
LiAlH4, alkyl- and aryllithiums without further reac-
tion (entries 1–4). Acyl anion equivalents, 2-lithio-1,3-
dithianes afforded the corresponding 6e and 6f in high
yield (entries 5 and 6). In addition, 5 reacted with
ketone, ester and amide enolates at the carbon a to
their carbonyl groups. Although only limited examples
have been reported for the SN2% reaction of 3,3,3-tri-
fluoropropene derivatives with ester enolates,9c,f
5
reacted not only with amide and ketone enolates
(entries 7 and 8), but even with the less reactive mal-
onate anion (entry 9). A nitrogen nucleophile also
underwent the SN2% reaction of 5 to give 3,3-difluoroal-
lylamine 6j in good yield (entry 10).
The results of the SN2% reaction of 5 with various
nucleophiles encouraged us to investigate the next step,
substitution of the silyl group. It is known that
dimethylphenylsilyl–vinylic carbon bonds are cleaved
with n-Bu4NF (TBAF) under relatively harsh condi-
tions.15 The removal of the silyl group in 6c, however,
proceeded very smoothly under mild conditions on
treatment with moist THF solution of n-Bu4NF, lead-
ing to monosubstituted difluoroalkene 7c in 99% yield
(Scheme 3).
We also examined the substitution of bromine atom for
the silyl group. When 6c was treated with bromine,
dibromide 8c was obtained in low yield due to its
instability.16 Successive treatment of 6c with bromine
and n-Bu4NF without isolation of 8c smoothly effected
dibromination and elimination of a silyl bromide to
give 2,2-difluorovinyl bromide 9c, a useful building
block, in 87% yield (Scheme 4).
Scheme 3.
Scheme 4.
Furthermore, CꢀC bond formation was effected by
utilizing the vinylic silicon of 6. Treatment of 6b with
benzaldehyde and n-Bu4NF afforded difluorinated
Scheme 2.

J. Ichikawa et al. / Tetrahedron Letters 44 (2003) 707–710
709
groups in a one-pot operation (entries 2 and 3). We also
achieved the one-pot synthesis of difluoroallylic alcohol
10b as shown in Scheme 6.20
allylic alcohol 10b in 22% yield along with 1,1-difluoro-
1-heptene (51% yield determined by 19F NMR).17,18 The
yield of 10b was improved by using tris(diethyl-
amino)sulfonium difluorotrimethylsilycate (TASF)19
instead of n-Bu4NF up to 68% (Scheme 5).
We have established a new synthetic method of 1,1-
difluoro-1-alkenes with the introduction of two kinds of
groups by utilizing the following properties of the silyl
group: (i) its a-anion-stabilizing effect promotes the
SN2% reaction of 1-trifluoromethylvinylsilane 5 with
nucleophiles to construct 2,2-difluorovinylsilanes 6, and
(ii) the subsequent substitution of electrophiles for the
silyl group affords monosubstituted 1,1-difluoro-1-alke-
Next, we attempted to combine the SN2% process and
the substitution of silyl group, and eventually accom-
plished a one-pot synthesis of difluoroalkenes (Table 2).
On treatment of 5 with nucleophiles and then with
moist n-Bu4NF, the two-step sequence readily pro-
ceeded to yield the corresponding monosubstituted
difluoroalkenes 7. This sequence successfully allowed
the construction of difluoroalkenes bearing functional
nes 7, 2-bromo-1,1-difluoro-1-alkenes
difluoro-3-hydroxy-1-alkenes 10.
9 and 1,1-
Acknowledgements
We are grateful to TOSOH F-TECH, INC. for a
generous gift of 2-bromo-3,3,3-trifluoro-1-propene.
This work was supported in part by research fellowship
for young scientists from the Japan Society for the
Promotion of Science to H.F.
Scheme 5.
Table 2. One-pot synthesis of 1,1-difluoro-1-alkenes 7
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1
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