1-Trifluoromethylvinylsilane as a CF2=C--CH 2+ synthon: Synthesis of functionalized 1,1-difluoro-1-alkenes via isolable 2,2-difluorovinylsilanes

Article abstract of DOI:10.1021/jo034718j

Various 1,1-difluoro-1-alkenes such as monosubstituted 1,1-difluoro-1-alkenes, 2-bromo-1,1-difluoro-1-alkenes, and 3,3-difluoroallylic alcohols are synthesized in two simple steps from 1-trifluoro-methylvinylsilane: (i) its S_N2′ reaction with n

Full text of DOI:10.1021/jo034718j

1-Tr iflu or om eth ylvin ylsila n e a s a CF 2dC--CH2 Syn th on :
+
Syn th esis of F u n ction a lized 1,1-Diflu or o-1-a lk en es via Isola ble
2,2-Diflu or ovin ylsila n es
J unji Ichikawa,* Hiroki Fukui, and Yuichiro Ishibashi
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, J apan
junji@chem.s.u-tokyo.ac.jp
Received May 27, 2003
Various 1,1-difluoro-1-alkenes such as monosubstituted 1,1-difluoro-1-alkenes, 2-bromo-1,1-difluoro-
1-alkenes, and 3,3-difluoroallylic alcohols are synthesized in two simple steps from 1-trifluoro-
methylvinylsilane: (i) its SN2′ reaction with nucleophiles to construct 2,2-difluorovinylsilanes and
(ii) the subsequent substitution of electrophiles for the vinylic silyl group. The combination of these
two processes allows a one-pot synthesis of the functionalized 1,1-difluoro-1-alkenes starting from
1-trifluoromethylvinylsilane, which functions as a CF2dC--CH2 synthon.
+
In tr od u ction
Fluorine-containing molecules are finding increasing
utility in various fields such as pharmaceutical and
agricultural chemistry and material science.1 Among
these compounds, 1,1-difluoro-1-alkenes are of special
interest, due to their diverse utility as building blocks
for fluorinated compounds and polymers.2 The activity
of these compounds as new types of enzyme inhibitors1d,e
and pesticides3 has also attracted much attention in
recent years. Although a number of examples of the
preparation of 1,1-difluoro-1-alkenes have been re-
ported,2,4 the generality of these methods is still limited.
The development of general synthetic methods for highly
functionalized 1,1-difluoro-1-alkenes remains a challenge
of practical importance.
F IGURE 1. gem-Difluorovinylmetals stabilized by an R-posi-
tion electron-withdrawing group.
electron-withdrawing group5 such as an oxygen-contain-
ing group,6 a halogen,7 a trifluoromethyl group,8 or an
aryl group9 (Figure 1). These substituents are needed to
enhance the thermal stability of 1 against â-elimination
of the metal fluoride leading to 1-fluoro-1-alkynes.5,10,11
Thus, very few reactive 2,2-difluorovinylmetals lacking
an R-anion-stabilizing group at the 1-position have been
One straightforward route to their synthesis involves
the generation and reaction of 2,2-difluorovinylmetals.4,5
Most reported difluorovinylmetals 1 reactive enough to
act as a vinyl anion, however, incorporate an R-position
(5) For reviews, see: (a) Brisdon, A. K.; Banger, K. K. J . Fluorine
Chem. 1999, 100, 35. (b) Coe, P. L. J . Fluorine Chem. 1999, 100, 45.
(c) Burton, D. J .; Yang, Z.-Y.; Morken, P. A. Tetrahedron 1994, 50.
2993. (d) Normant, J .-F. J . Organomet. Chem. 1990, 400, 19.
(6) (a) Nakai, T.; Tanaka, K.; Ishikawa, N. Chem. Lett. 1976, 1263.
(b) Tanaka, K.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1978, 19,
4809. (c) Crowly, P. J .; Howarth, W. M.; Owton, W. M.; Percy, J . M.;
Stansfield. K. Tetrahedron Lett. 1996, 37, 5975. (d) Lee, J .; Tsukazaki,
M.; Snieckus, V. Tetrahedron Lett. 1993, 34, 415. (e) Patel, S. T.; Percy,
J . M.; Wilkens, R. D. J . Org. Chem. 1996, 61, 166. (f) Metcalf, B. W.;
J arvi, E. T.; Burkhart, J . P. Tetrahedron Lett. 1985, 26, 2861. (g)
Allcock, H. R.; Suszko, P. R.; Evans, T. L. Organometallics 1982, 1,
1443.
(7) (a) Burdon, J .; Coe, P. L.; Haslock, I. B.; Powell, R. L. J . Fluorine
Chem. 1999, 99, 127. (b) Banger, K. K.; Brisdon, A. K.; Gupta, A. Chem.
Commun. 1997, 139. (c) Burdon, J .; Coe, P. L.; Haslock, I. B.; Powell,
R. L. Chem. Commun. 1996, 49. (d) Anilkumar, R.; Burton, D. J .
Tetrahedron Lett. 2002, 43, 2731. (e) Brown, S. J .; Corr, S.; Percy, J .
M. Tetrahedron Lett. 2000, 41, 5269. (f) Bainbridge, J . M.; Brown, S.
J .; Ewing, P. N.; Gibson, R. R.; Percy, J . M. J . Chem. Soc., Perkin Trans.
1 1998, 2541. (g) Burdon, J .; Coe, P. L.; Haslock, I. B.; Powell, R. L. J .
Fluorine Chem. 1997, 151. (h) Anilkumar, R.; Burton, D. J . Tetrahedron
Lett. 2002, 43, 6979. (i) Shigeoka, T.; Kuwahara, Y.; Watanabe, K.;
Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J . Fluorine Chem. 2000,
103, 99. (j) Nguyen, B. V.; Burton D. J . J . Org. Chem. 1998, 63, 1714.
(8) Morken, P. A.; Burton D. J . J . Org. Chem. 1993, 58, 1167.
(9) Ishihara, T.; Yamana, M.; Ando, T. Tetrahedron Lett. 1983, 24,
5657.
* Address correspondence to this author. Phone/fax: +81-3-5841-
4345.
(1) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Organofluorine Compounds in
Medicinal Chemistry and Biochemical Applications; Filler, R., Koba-
yashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, The Neth-
erlands, 1993. (c) Organofluorine Chemistry: Principles and Commer-
cial Applications; Banks, R. E., Tatlow, J . C., Smart, B. E., Eds; Plenum
Press: New York, 1994. (d) Selective Fluorination in Organic and
Bioorganic Chemistry; ACS Symp. Ser. No. 456; Welch, J . T., Ed.;
American Chemical Society: Washington, DC, 1991. (e) Biomedical
Frontiers of Fluorine Chemistry; ACS Symp. Ser. No. 639; Ojima, I.,
McCarthy, J . R., Welch, J . T., Eds.; American Chemical Society:
Washington, DC, 1996. (f) Resnati, G. Tetrahedron 1993, 49, 9385.
(2) (a) Tozer, M. J .; Herpin, T. F. Tetrahedron 1996, 52, 8619. (b)
Percy, J . M. Contemp. Org. Synth. 1995, 2, 251.
(3) (a) Hatano, K.; Nakamoto, Y.; Umeyama, H.; Noritake, T. J P
2001288142, 2001; Chem. Abstr. 2001, 135, 303602. (b) Fujii, K.;
Hatano, K.; Tsutsumiuchi, K.; Nakamoto, Y. J P 2000198769, 2000;
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T. WO 9962866, 1999; Chem. Abstr. 2000, 132, 22762. (d) Fujii, K.;
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9952874, 1999; Chem. Abstr. 1999, 131, 271889.
(4) Ichikawa, J . J . Fluorine Chem. 2000, 105, 257 and references
therein.
10.1021/jo034718j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/04/2003
7800
J . Org. Chem. 2003, 68, 7800-7805

Synthesis of Functionalized 1,1-Difluoro-1-alkenes
SCHEME 1. Diflu or oa lk en e Syn th esis via Non sta bilized 2,2-Diflu or ovin ylm eta ls
SCHEME 2. Syn th etic Str a tegy tow a r d
1,1-Diflu or o-1-a lk en es
Resu lts a n d Discu ssion
(a ) Syn th etic Str a tegy tow a r d 1,1-Diflu or o-1-a lk -
en es. 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,14 our investigation
started with the development of a widely applicable
synthetic route to these compounds.
1-Trifluoromethylvinyl compounds are known to react
with nucleophiles in an SN2′ fashion to afford 1,1-difluoro-
1-alkenes.15 The following limitations of this reaction,
however, have restricted its applicability: the necessity
of (i) an electron-withdrawing group such as a carbonyl
or an aryl group on the 2-position of the 3,3,3-trifluoro-
propene framework and/or (ii) highly reactive nucleo-
philes such as alkyllithiums. For example, it has been
reported that 5-phenyl-2-trifluoromethyl-1-pentene which
had an alkyl group on the 2-position reacted with
butyllithium to give the corresponding difluoroalkene,
while no reaction was observed with phenyllithium.15d
We expected that (i) utilizing the R-anion-stabilizing
effect of silicon could overcome these drawbacks to
support the generation of intermediary anion 5 and
therefore to promote the SN2′ reaction16 and that at the
same time (ii) the reaction would provide a solution to
the synthesis of 2,2-difluorovinylsilanes desired above.
Furthermore, the resulting vinylsilanes 6 would allow
in turn the introduction of the second substituent by the
replacement of the silyl group.17 Thus, as depicted in
Scheme 2 the sequence of reactions starting from 1-tri-
fluoromethylvinylsilanes 4 could provide a wide variety
of 1,1-difluoro-1-alkenes 7 bearing two kinds of substit-
uents (Nu, E). In this sequence, 1-trifluoromethylvinyl-
SCHEME 3. P r ep a r a tion of
Dim eth ylp h en yl(1-tr iflu or om eth ylvin yl)sila n e (8)
described. As a solution to this problem, we have already
developed thermostable 2,2-difluorovinylboron 2 and
-zirconium 3 species to achieve the difluoroalkene syn-
thesis via transmetalation to copper and zinc intermedi-
ates, respectively (Scheme 1).4 Thermostable, unsubsti-
tuted 2,2-difluorovinylzinc reagent also has been reported
by Burton.12
In terms of thermal stability the corresponding silicon
species, 2,2-difluorovinylsilanes, also attracted our at-
tention and prompted us to investigate their chemistry.
Eventually, we developed the synthetic method for 1,1-
difluoro-1-alkenes via 2,2-difluorovinylsilanes, which con-
sists of two steps: the construction and the reaction of
difluorovinylsilanes (vide infra). The preliminary results
of this approach have been briefly reported in our
previous communication, where the first step was treated
mainly (Tables 1 and 2) along with a few examples of
the second step.13 Combining the results of the second
step (Table 3) and their one-pot reaction (Table 4) with
those published earlier by us, we present here a full
account of our studies on the synthesis of 1,1-difluoro-
1-alkenes starting from 1-trifluoromethylvinylsilane via
2,2-difluorovinylsilanes, which are quite stable, easy to
handle, and can be stored under air.
+
silanes 4 function as CF2dC--CH2 synthons.
(b) Syn th esis of 1,1-Diflu or o-1-a lk en es. In the SN2′
reaction of â-silyl allylic ethers, a phenyl group on the
(14) (a) Okano, T.; Ito, K.; Ueda, T.; Muramatsu, H. J . Fluorine
Chem. 1986, 32, 377. (b) Xu, Y.; J in, F.; Huang, W. J . Org. Chem. 1994,
59, 2638.
(15) For the SN2′ reaction of 1-trifluoromethylvinyl compounds
[CH2dC(Y)CF3], see: Y ) CO2R (CO2H): (a) Kitazume, T.; Ohnogi,
T.; Miyauchi, H.; Yamazaki, T. J . Org. Chem. 1989, 54, 5630. (b)
Fuchikami, T.; Shibata, Y.; Suzuki, Y. Tetrahedron Lett. 1986, 27, 3173.
Y ) SPh, SePh: (c) Feiring, A. E. J . Org. Chem. 1980, 45, 1962. Y )
Ph: (d) Be´gue´, J .-P.; Bonnet-Delpon, D.; Rock, M. H. J . Chem. Soc.,
Perkin Trans. 1 1996, 1409. Y ) H (Me): (e) Hiyama T.; Obayashi,
M.; Sawahata, M. Tetrahedron Lett. 1983, 24, 4113. (f) Kendrick, D.
A.; Kolb, M. J . Fluorine Chem. 1989, 45, 265. (g) Bergstrom, D. E.;
Ng, M. W.; Wong, J . J . J . Org. Chem. 1983, 48, 1902.
(16) The favorable effect of an R-silyl group in R,â-unsaturated
enones on the Michael reaction is well documented. Stork, G.; Ganem,
B. J . Am. Chem. Soc. 1973, 95, 6152.
(17) (a) Weber, W. P. Silicon Reagents for Organic Synthesis;
Splinger: Berlin, Germany, 1983. (b) Colvin, E. W. Silicon in Organic
Synthesis; Butterworth: London, UK, 1981.
(10) Runge, A.; Sander, W. W. Tetrahedron Lett. 1990, 31, 5453.
(11) For example, unsubstituted 2,2-difluorovinyllithium should be
generated at -110 °C and undergoes a smooth â-elimination even at
-80 °C.5d
(12) Nguyen, B. V.; Burton, D. J . J . Org. Chem. 1997, 62, 7758.
(13) Ichikawa, J .; Ishibashi, Y.; Fukui, H. Tetrahedron Lett. 2003,
44, 707.
J . Org. Chem, Vol. 68, No. 20, 2003 7801

Ichikawa et al.
TABLE 1. SN2′ Rea ction of 8 w ith Nu cleop h iles
a
b
N,N,N′,N′-Tetramethylethylenediamine (1.0 equiv) was used. DMF was used as solvent.
SCHEME 4. P r otod esilyla tion of 9c
We then investigated the SN2′ reaction of 8 with
various nucleophiles. The results are summarized in
Table 1. SN2′ products 9 were obtained in excellent yield
for LiAlH4 and alkyl- and aryllithiums without overreac-
tion, the substitution of the vinylic fluorines in 9 via
addition-elimination process (entries 1-4).21,22 Acyl
anion equivalents, 2-lithio-1,3-dithianes, afforded the
silicon has been reported to play an important role in
raising their reactivity.18 Taking into consideration its
boiling point as well as the SN2′ reactivity, we adopted
dimethylphenylsilyl group for 4. After some attempts, we
found that the in situ generated 1-trifluoromethylvinyl-
magnesium bromide19 was efficiently trapped with dim-
ethylphenylsilyl chloride to afford 8 in 80% yield (Scheme
3). Thus obtained 8 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
â-elimination generating 1,1-difluoroallene.20
(20) Drakesmith, F. G.; Stewart, O. J .; Tarrant, P. J . Org. Chem.
1968, 33, 280.
(21) (a) Smart, B. E. In Organofluorine Chemistry, Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J . C.,
Eds.; Plenum: New York, 1994; p 57. (b) Lee, V. J . In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, UK, 1991;
Vol. 4, p 69. (c) Ichikawa, J .; Wada, Y.; Fujiwara, M.; Sakoda, K.
Synthesis 2002, 1917 and references therein.
(22) The replacement of the vinylic fluorines in 9b by n-BuLi readily
proceeded at -45 °C to give 5-fluoro-6-dimethylphenylsilyl-5-undecene
in 93% yield (E:Z ) 12:88). The same reaction of 1,1-difluoro-2-phenyl-
1-hexane with n-BuLi occurred at -45 °C to afford 5-fluoro-6-phenyl-
5-decene in 95% yield (E:Z ) 69:31). These results reveal that the effect
of silicon works as favorably as that of the phenyl group in the sub-
stitution of the vinylic fluorines. The stereochemistry of the E and Z
isomers was determined by NOESY spectroscopy. See also: (a) Martin,
S.; Sauveˆtre, R.; Normant, J .-F. Tetrahedron Lett. 1983, 24, 5615. (b)
Huang, X.-h.; He, P.-y.; Shi, G.-q. J . Org. Chem. 2000, 65, 627.
(18) Kishi, N.; Imma, H.; Mikami, K.; Nakai, T. Synlett 1992, 189.
(19) The Grignard reagent was prepared from 2-bromo-3,3,3-tri-
fluoro-1-propene in the presence of an electrophile. J iang, B.; Wang,
Q.-F.; Yang, C.-G.; Xu, M. Tetrahedron Lett. 2001, 42, 4083.
7802 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of Functionalized 1,1-Difluoro-1-alkenes
TABLE 2. On e-P ot Syn th esis of Mon osu bstitu ted 1,1-Diflu or o-1-a lk en es 10
TABLE 3. Syn th esis of 3,3-Diflu or oa llylic Aceta tes 14
SCHEME 5. Br om od esilyla tion of 9c
SCHEME 6. Rea ction of 9b w ith Ald eh yd e
corresponding 9e and 9f in high yield (entries 5 and 6).
In addition, 8 reacted with ketone, ester, and amide
enolates at the carbon R to their carbonyl groups.
Although only limited examples have been reported for
the SN2′ reaction of 1-trifluoromethylvinyl compounds
with ester enolates,15c,f 8 reacted not only with amide and
ketone enolates (entries 7 and 8) but even with the less
reactive malonate anion (entry 9). These results clearly
show that 8 is much more reactive than R-(trifluoro-
methyl)styrene bearing a phenyl group instead of the silyl
group.15d,22 Nitrogen nucleophiles derived from secondary
and primary amines also underwent the SN2′ reaction of
8 to give 3,3-difluoroallylamines 9j and 9k in 86% and
50% yields, respectively (entries 10 and 11).
The results of the SN2′ reaction of 8 with various
nucleophiles encouraged us to investigate the next step,
substitution of the silyl group. It is known that dimeth-
ylphenylsilyl-vinylic carbon bonds are cleaved with
tetrabutylammonium fluoride (n-Bu4NF, TBAF) under
relatively harsh conditions (at 80 °C in DMSO).23 The
removal of the silyl group in 9c, however, proceeded
smoothly even at room temperature on treatment with
a moist THF solution of n-Bu4NF,24 leading to monosub-
stituted difluoroalkene 10a in 99% yield (Scheme 4).
a
b
Not isolated. Yield was determined by 19F NMR. 3-Phenyl-
propanal (1.2 equiv), TASF (1.2 equiv), and acetic anhydride (1.5
equiv) were used.
Next, attempted combination of the SN2′ process and
the above-mentioned protodesilylation gave rise to a one-
pot synthesis of difluoroalkenes. On treatment of 8 with
nucleophiles and then with moist n-Bu4NF, the two
processes successively proceeded to yield the correspond-
ing monosubstituted difluoroalkenes 10 (Table 2). This
one-pot sequence was successfully applied to the con-
struction of difluoroalkenes bearing functional groups
such as 1,3-dithiane and amide moieties (entries 2 and
3).
We also examined the substitution of bromine atom
for the vinylic silyl group.17 When 9c was treated with
bromine, dibromide 11 was obtained in low yield due to
its instability.25 Successive treatment of 9c with bromine
(23) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 2877.
(24) The THF solution of n-Bu4NF (1.0 M) contained water (10 vol
%).
(25) Sayferth, D.; Wada, T.; Maciel, G. E. Inorg. Chem. 1962, 1, 232.
J . Org. Chem, Vol. 68, No. 20, 2003 7803

Ichikawa et al.
TABLE 4. On e-P ot Syn th esis of 3,3-Diflu or oa llylic Aceta tes 14
and n-Bu4NF without isolation of 11 smoothly effected
dibromination and elimination of a silyl bromide to give
2,2-difluorovinyl bromide 12, a useful building block, in
87% yield (Scheme 5).
acetates 14 in good yield. Thus, this methodology pro-
vides a new entry to highly functionalized 1,1-difluoro-
1-alkenes.
Con clu sion
Furthermore, C-C bond formation was investigated
by utilizing the vinylic silicon.26 While there are several
reports on the fluoride-promoted reaction of vinylsilanes
with aldehydes, all of these vinylsilanes have an R-posi-
tion anion-stabilizing group such as a carbonyl and cyano
group,27 a phenyl group,23 and a halogen.28 Despite lack
of an anion-stabilizing group, 9b was treated with
benzaldehyde and n-Bu4NF to afford difluoroallylic al-
cohol 13a in 22% yield along with 1,1-difluoro-1-heptene
(51% yield determined by 19F NMR). The yield of 13a was
improved up to 68% by using tris(diethylamino)sulfonium
difluorotrimethylsilycate (TASF)29 instead of n-Bu4NF
(Scheme 6).30 Since difluoroallylic alcohols 13 were easily
hydrolyzed via the allylic cations leading to R,â-unsatur-
ated acids under acidic conditions, we isolated the
products as the corresponding acetates 14 (Table 3).
Compared to aromatic aldehydes, an aliphatic aldehyde
gave the corresponding acetate 14d in lower yield (entry
4), due to the self-aldol reaction.
We have established a new synthetic method for 1,1-
difluoro-1-alkenes with the introduction of two kinds of
groups in different polarities by utilizing the following
properties of the silyl group: (i) Its R-anion-stabilizing
effect promotes the SN2′ reaction of 1-trifluoromethylvi-
nylsilane 8 with nucleophiles to construct 2,2-difluorovi-
nylsilanes 9, and (ii) the subsequent substitution of
electrophiles for the silyl group affords monosubstituted
1,1-difluoro-1-alkenes 10, 2-bromo-1,1-difluoro-1-alkenes
12, and 3,3-difluoroallylic alcohols 13 or their acetates
14. In this process, 8 turns out to function as a versatile
+
CF2dC--CH2 synthon, opening an efficient access to
functionalized 1,1-difluoro-1-alkenes.
Exp er im en ta l Section
(2,2-Diflu or o-1-m eth ylvin yl)dim eth ylph en ylsilan e (9a).
To a suspension of lithium aluminum hydride (152 mg, 0.500
mmol) in THF (8 mL) was added 8 (462 mg, 2.00 mmol) in
THF (2 mL) over 10 min at -78 °C under argon. After the
reaction mixture was stirred at 0 °C for 5 h, the reaction was
quenched with MeOH (4 mL) and aqueous HCl (10 mL, 2 M).
Organic materials were extracted with Et2O (10 mL × 3). The
combined extracts were washed with brine and then dried over
MgSO4. After removal of the solvent under reduced pressure
(30 kPa), the residue was purified by PTLC (pentane) to give
9a (374 mg, 88%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
δ 0.41 (3H, s), 0.42 (3H, s), 1.52 (3H, dd, J HF ) 2.3, 2.3 Hz),
7.35-7.38 (3H, m), 7.50-7.52 (2H, m). 13C NMR (126 MHz,
CDCl3) δ -2.9, 10.5 (dd, J CF ) 6, 6 Hz), 75.7 (dd, J CF ) 30, 2
Hz), 127.9, 129.3, 133.7, 137.1, 155.8 (dd, J CF ) 305, 281 Hz).
19F NMR (471 MHz, CDCl3) δF 84.3 (1F, d, J FF ) 37 Hz), 88.0
(1F, d, J FF ) 37 Hz). IR (neat) 1697, 1221, 1090, 812, 775, 731,
698 cm-1. Anal. Calcd for C11H14F2Si: C, 62.23; H, 6.65.
Found: C, 62.05; H, 6.71.
The one-pot synthesis of difluoroallylic acetates 14 was
accomplished by the combination of the SN2′ process and
the reaction with benzaldehyde, followed by acetylation
(Table 4). On treatment of 8 with nucleophiles and then
benzaldehyde and TASF, followed by Ac2O and Et3N, the
three-step sequence including two C-C bond formations
proceeded readily to yield the desired difluoroallylic
(26) Mikami, K.; Wakabayashi, H.; Nakai, T. J . Org. Chem. 1991,
56, 4337 and references therein.
(27) (a) Matsumoto, K.; Oshima, K.; Utimoto, K. Chem. Lett. 1994,
1211. (b) Sato, Y.; Takeuchi, S. Synthesis 1983, 734. (c) Sato, Y.; Hitomi,
K. J . Chem. Soc., Chem. Commun. 1983, 170.
(28) For the reaction of fluorinated vinylsilanes with aldehydes,
see: (a) Hanamoto, T.; Harada, S.; Shindo, K.; Kondo, M. Chem.
Commun. 1999, 2397. (b) Yudin, A. K.; Prakash, G. K. S.; Deffieux,
D.; Bradley, M.; Bau, R.; Olah, G. A. J . Am. Chem. Soc. 1997, 119,
1572. (c) Fujita, M.; Obayashi, M.; Hiyama, T. Tetrahedron 1988, 44,
4135. (d) Martin, S.; Sauveˆtre, R.; Normant, J .-F. J . Organomet. Chem.
1984, 264, 155.
(29) Fujita, M.; Hiyama, T. Org. Synth. 1990, 69, 44.
(30) For reports on the utility of 3,3-difluoroallylic alcohols, see:
Patel, S. T.; Percy, J . M.; Wilkens, R. D. J . Org. Chem. 1996, 61, 166
and references therein.
1,1-Diflu or o-1-tr id ecen e (10a ). To a solution of 9c (177
mg, 0.50 mmol) was added n-Bu4NF (TBAF, 0.44 mL, 1.0 M
in THF, 0.44 mmol) at 0 °C under argon. The reaction mixture
was stirred for 12 h at room temperature. Phosphate buffer
(pH 7) was added to quench the reaction, and organic materials
were extracted with Et2O (10 mL × 3). The combined extracts
7804 J . Org. Chem., Vol. 68, No. 20, 2003

Synthesis of Functionalized 1,1-Difluoro-1-alkenes
were washed with brine and dried over MgSO4. After removal
of the solvent under reduced pressure (30 kPa), the residue
was purified by PTLC (hexane) to give 10a (106 mg, 99%) as
The reaction mixture was stirred at room temperature for 2
h, and then treated with Et3N (1 mL) and acetic anhydride
(61.3 µL, 0.65 mmol). After the mixture was stirred for 1 h at
room temperature, phosphate buffer (pH 7) was added to
quench the reaction. Organic materials were extracted with
AcOEt (10 mL × 3), and the combined extracts were washed
with brine and dried over MgSO4. After removal of the solvent
under reduced pressure, the residue was purified by PTLC
(hexane-AcOEt 10:1) to give 14a (88 mg, 63%) as a pale yellow
oil. 1H NMR (500 MHz, CDCl3) δ 0.82 (3H, t, J ) 7.1 Hz), 1.14-
1.23 (5H, m), 1.28-1.30 (1H, m), 1.83-1.85 (1H, m), 1.92-
1.94 (1H, m), 2.17 (3H, s), 6.63 (1H, br s), 7.28-7.30 (3H, m),
7.34-7.37 (2H, m). 13C NMR (126 MHz, CDCl3) δ 13.9, 22.1,
22.2, 23.4, 28.1, 31.4, 71.9 (d, J CF ) 7 Hz), 90.3 (dd, J CF ) 19,
12 Hz), 125.6, 127.8, 128.5, 138.1, 154.9 (dd, J CF ) 291, 289
1
a colorless oil. H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J )
7.0 Hz), 1.26-1.35 (17H), 1.96 (2H, br dt, J ) 7.9, 7.9 Hz),
4.12 (1H, dtd, J FH ) 25.6 Hz, J ) 7.9 Hz, J FH ) 2.7 Hz). 13C
NMR (126 MHz, CDCl3) δ 14.1, 22.1 (d, J CF ) 4 Hz), 22.7, 28.9,
29.3, 29.4 (dd, J CF ) 2, 2 Hz), 29.4, 29.5, 29.6, 29.6, 31.9, 78.0
(dd, J CF ) 21, 21 Hz), 156.2 (dd, J CF ) 285, 285 Hz). 19F NMR
(471 MHz, CDCl3) δF 69.5 (1F, dd, J FF ) 50 Hz, J FH ) 26 Hz),
71.9 (1F, d, J FF ) 50 Hz). IR (neat) 3725, 2924, 2854, 1747,
914, 744 cm-1. Anal. Calcd for C13H24F2: C, 71.52; H, 11.08.
Found: C, 71.31; H, 11.18.
On e-p ot r ea ction fr om 8: To a solution of 1-iododecane
(323 mg, 1.20 mmol) in Et2O (1.2 mL) was added t-BuLi (1.70
mL, 1.5 M in pentane, 2.55 mmol) over 5 min at -78 °C under
argon. After being stirred at room temperature for 1 h, the
reaction mixture was added to a solution of 8 (232 mg, 1.01
mmol) in THF (5 mL) at -78 °C over 5 min. After the reaction
mixture was stirred at -78 °C for 20 min, n-Bu4NF (2.00 mL,
1.0 M in THF, 2.00 mmol) was added. The resulting mixture
was stirred at room temperature for 4 h. Phosphate buffer (pH
7) was added to quench the reaction, and organic materials
were extracted with Et2O (5 mL × 3). The combined extracts
were washed with brine and dried over MgSO4. After removal
of the solvent under reduced pressure (30 kPa), the residue
was purified by PTLC (hexane) to give 10a (179 mg, 82%) as
a colorless oil.
2-Br om o-1,1-d iflu or o-1-tr id ecen e (12). To a solution of
9c (356 mg, 1.01 mmol) in CH2Cl2 (8 mL) was added bromine
(60 µL, 1.17 mmol) in CH2Cl2 (2 mL) at -78 °C over 3 h under
argon. After the reaction mixture was stirred at 0 °C for 30
min, n-Bu4NF (1.10 mL, 1.0 M in THF, 1.10 mmol) was added.
The mixture was stirred at 0 °C for 1 h, and phosphate buffer
(pH 7) was added to quench the reaction. Organic materials
were extracted with CH2Cl2 (10 mL × 3). The combined
extracts were washed with brine and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue
was purified by PTLC (hexane) to give 12 (262 mg, 87%) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J ) 7.0
Hz), 1.21-1.32 (17H, m), 1.52 (2H, br t, J ) 7.0 Hz), 2.43 (1H,
m). 13C NMR (126 MHz, CDCl3) δ 14.0, 22.7, 27.2 (d, J CF ) 2
Hz), 28.3, 29.2, 29.4, 29.5, 29.6, 29.6, 30.6, 31.9, 81.2 (dd, J CF
) 41, 20 Hz), 153.2 (dd, J CF ) 287, 283 Hz). 19F NMR (471
MHz, CDCl3) δF 70.8 (1F, dd, J FF ) 44 Hz, J HF ) 3 Hz), 77.1
(1F, d, J FF ) 44 Hz). IR (neat) 2922, 2852, 1267, 1173, 960,
771 cm-1. Anal. Calcd for C13H23BrF2: C, 52.42; H, 7.74.
Found: C, 52.53; H, 7.80.
Hz), 169.6. 19F NMR (471 MHz, CDCl3) δF 70.7 (1F, d, J FF
)
42 Hz), 72.5 (1F, d, J FF ) 42 Hz). IR (neat) 2956, 2931, 2866,
1747, 1371, 1265, 1227, 1328, 1018 cm-1. Anal. Calcd for
C
16H20F2O2: C, 68.07; H, 7.14. Found: C, 68.07; H, 7.22.
On e-p ot r ea ction fr om 8: To a solution of 8 (117 mg, 0.509
mmol) in THF (4 mL) was added n-BuLi (0.39 mL, 1.55 M in
hexane, 0.60 mmol) at -78 °C under argon. After the reaction
mixture was stirred for 20 min, benzaldehyde (66 µL, 0.65
mmol) and TASF (0.75 mL, 1.0 M in THF, 0.75 mmol) were
successively added. The reaction mixture was stirred at room
temperature for 2.5 h, and then treated with Et3N (1 mL) and
acetic anhydride (71 µL, 0.75 mmol). The mixture was stirred
at room temperature for 1 h, and phosphate buffer (pH 7) was
added to quench the reaction. Organic materials were ex-
tracted with AcOEt (10 mL × 3). The combined extracts were
washed with brine and dried over MgSO4. After removal of
the solvent under reduced pressure, the residue was purified
by PTLC (hexane-AcOEt 10:1) to give 14a (97 mg, 67%) as a
pale yellow oil.
Ack n ow led gm en t. We are grateful to TOSOH F-
TECH, INC. for a generous gift of 2-bromo-3,3,3-
trifluoro-1-propene and financial support of this re-
search. Mr. Kenji Watanabe and Dr. Eri Fukushi (GC-
MS & NMR Laboratory, Faculty of Agriculture, Hokkaido
University) are thanked for recording the HR-MS
spectra. This work was supported in part by a research
fellowship for young scientists from the J apan Society
for the Promotion of Science to H.F.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for 8, 9b-k , 10b,c, 13a , and
14b-f. This material is available free of charge via the
Internet at http://pubs.acs.org.
3,3-Diflu or o-2-pen tyl-1-ph en yl-2-pr open yl Acetate (14a).
To a solution of 9b (133 mg, 0.49 mmol) and benzaldehyde
(56 µL, 0.55 mmol) in THF (4 mL) was added TASF (0.55 mL,
1.0 M in THF, 0.55 mmol) at room temperature under argon.
J O034718J
J . Org. Chem, Vol. 68, No. 20, 2003 7805