Synthesis of trifluoro- or difluoromethylated olefins by regio- and stereocontrolled SN2′ reactions of gem-difluorinated vinyloxiranes

Article abstract of DOI:10.1021/jo060089c

This paper presents a highly stereoselective synthesis of trifluoro- or difluoromethylated olefins via an S_N2′ type fluorination or reductions of gem-difluorinated vinyloxiranes. Their fluorination with HF-Py furnished trifluoromethylated allyl

Full text of DOI:10.1021/jo060089c

Synthesis of Trifluoro- or Difluoromethylated Olefins by Regio- and
Stereocontrolled SN2′ Reactions of gem-Difluorinated Vinyloxiranes
Hisanori Ueki, Takashi Chiba, and Tomoya Kitazume*
Graduate School of Bioscience and Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, Japan
tkitazum@bio.titech.ac.jp
ReceiVed January 16, 2006
This paper presents a highly stereoselective synthesis of trifluoro- or difluoromethylated olefins via an
SN2′ type fluorination or reductions of gem-difluorinated vinyloxiranes. Their fluorination with HF-Py
furnished trifluoromethylated allylic alcohols with exclusive E selectivity. On the other hand, their reduction
with DIBAL-H afforded difluoromethylated E-allylic alcohols predominantly, whereas the corresponding
Z isomers were formed exclusively by treatment with BH3‚THF.
Introduction
reported to show different metabolic pathways depending on
the degree of fluorination.5 Moreover, fluoromethylated sulfo-
nanilides possess a herbicidal activity; among them, the tri-
fluoromethlated one is the most effective due to increasing
lipophilicity and electronegativity.6 Furthermore, fluoromethyl
ketones, which are known to inhibit acetylcholineesterase and
carboxylesterases, show an increase in activity as the degree of
fluorination increases,7 since fluorine substitution enhances the
stability of intermediate geminal diols or hydrates.8
However, in general, different synthetic strategies and dif-
ferent starting materials were necessary to prepare the useful
fluoromethylated compounds depending on the degree of
fluorination desired. Moreover, highly stereocontrolled synthetic
methods for the preparation of such compounds are sometimes
quite difficult.9 To overcome such drawbacks, we reported the
highly stereoselective introduction of fluorine-containing methyl
groups from a single starting compound by the application of
Introduction of fluorine atoms into organic molecules often
significantly alters the physical, chemical, and biological
properties of the compounds.1 Among fluorinated compounds,
fluoromethylated (-CH3-nFn; n ) 1, 2, 3) compounds are the
most fundamental and widely used, since the degree of
fluorination in such groups is sometimes significantly important,
especially in the medicinal and agrochemical field.1,2 For
instance, monofluoroacetic acid possesses a high toxicity,
inhibiting the aconitase activity in the TCA cycle, whereas di-
and trifluoroacetic acids do not exhibit such inhibition3 because
of the altered steric and electronic properties by the substitution
of a hydrogen with a fluorine atom.2b,4 On the other hand,
â-fluoroalanines are well-known as suicide substrates, and are
(1) (a) Hiyama, T. Organofluorine Compounds. Chemistry and Applica-
tions; Springer-Verlag: Berlin, Germany, 2000. (b) Kitazume, T.; Yamazaki,
T. Experimental Methods in Organic Fluorine Chemistry: Kodansya:
Tokyo, Japan, 1998.
(2) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds. Biomedical Frontiers
of Fluorine Chemistry; ACS Symp. Ser. No. 639; American Chemical
Society: Washington, DC, 1996. (b) Smart, B. E. J. Fluorine Chem. 2000,
109, 3.
(5) Wang, E. A.; Walsh, C. Biochemistry 1981, 20, 7539.
(6) Yoshioka, H.; Takayama, C.; Matsuo, N. Yuki Gousei Kagaku
Kyokaishi 1984, 42, 809.
(7) (a) Wheelock, C. E.; Colvin, M. E.; Uemura, I.; Olmstead, M. M.;
Sanborn, J. R.; Nakagawa, Y.; Jones, A. D.; Hammock, B. D. J. Med. Chem.
2002, 45, 5576. (b) Allen, K. N.; Abeles, R. H. Biochemistry 1989, 28,
8466.
(8) (a) Linderman, R. J.; Tennyson, S. D.; Shultz, D. A. Tetrahedron
Lett. 1994, 35, 6437. (b) Linderman, R. J.; Jamois, E. A. J. Fluorine Chem.
1991, 53, 79.
(3) Walsh, C. AdV. Enzymol. 1983, 55, 197.
(4) The trifluoromethyl group is often claimed to be at least as large as
the isopropyl group, see: (a) Schlosser, M.; Michel, D. Tetrahedron 1996,
52, 99. (b) MacPhee, J. A.; Panaye, A.; Dubois, J.-E. Tetrahedron 1978,
34, 3553. (c) Schlosser, M. Angew. Chem., Int. Ed. 1998, 110, 1496.
10.1021/jo060089c CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/05/2006
3506
J. Org. Chem. 2006, 71, 3506-3511

SN2′ Reaction, Fluorination, Reduction
TABLE 1. Fluorination of 1a with Fluorinating Reagentsa
entry
reagent
TBAF
conditions
yield of 2a (%)
E/Z
1
2
3
4
5
THF, rt, 24 h
b
-/-
80/20
88/12
>99/<1
>99/<1
THF, reflux, 24 h
CH3CN, reflux, 7 h
DMF, 100 °C, 1.5 h
CH2Cl2, 0 °C, 1 h
>55
>58
>38
>99
FIGURE 1. Various difluorinated vinyloxiranes 1a-k.
HF-Py
a Yields and ratios were determined by 19F NMR. b No reaction.
SCHEME 1
the full details of the preparation of di- and trifluoromethylated
olefins from a key synthetic intermediate, gem-difluorinated
vinyloxiranes, are described.
Results and Discussion
Selective SN2′ Fluorination of gem-Difluorinated Vinyl-
oxiranes. As we reported previously,13a an SN2′ type fluorination
of 1a by MgF2 as well as LiF/AcOH resulted in the complete
recovery of the starting material, while selective SN2′ bromi-
nations and chlorinations were realized under similar conditions.
Such drawbacks prompted us to investigate their reactivity
utilizing several fluorinating reagents (Table 1). The application
of KF and CsF failed to provide the corresponding products
even at high temperature and prolonged reaction times. KHF2,
which is often used for oxirane-opening reactions,17 also
demonstrated poor reactivity, even in the presence of 12-crown-4
or Ph3P.18 Although no product was observed with the applica-
tion of TBAF (tetrabutylammonium fluoride) at ambient tem-
perature, complete consumption of 1a and formation of an E,Z
mixture of the SN2′ product 2a was observed at higher
temperature (entries 1 and 2). Unfortunately the products were
not easy to isolate from unidentified byproducts. Also the
application of other solvents yielded similar results (entries 3
and 4). On the other hand, further fluorination to the OH moiety
of 2a occurred to afford tetrafluorinated compound 3, when
DAST (diethylaminosulfur trifluoride) and Ishikawa reagent
(hexafluoropropene diethylamine)19 were employed as a fluori-
nating reagent (Scheme 2).20 As we reported previously,13a
strong Brønsted acids, with pKa, which is lower than 4.0, can
react with 1a smoothly in an SN2′ manner to afford E-allylic
alcohols exclusively. Inspired by these experimental facts, we
decided to conduct the reaction with HF-Py,21 which is
frequently used for an oxirane-opening fluorination,22,23 and the
desired trifluorinated allylic alcohol was obtained in quantitative
yield with exclusive E selectivity (entry 5).
the readily available D-glucose with gem-difluoroolefine as a
key intermediate.10
Recently, we have established the preparation of gem-
difluorinated vinyloxiranes 1a-k (Figure 1) which have sig-
nificant potential as versatile building blocks for fluorinated
compounds, utilizing their intrinsic reactivity.11 Although they
possess three reaction sites for nucleophiles, we have demon-
strated their ability to undergo highly regio- and stereoselective
reactions depending on the employed organometallic re-
agents11,12 or halogenating reagents.13 Very recently, we reported
selective synthesis of difluoromethylated olefins utilizing SN2′
reductions of gem-difluorinated vinyloxiranes, generally pro-
ceeding with a high level of regio- and stereocontrol.14 These
successful results prompt us to investigate their regio- and
stereoselective reductions and fluorinations for the synthesis of
fluoromethylated olefins (Scheme 1), since their selective
syntheses are not particularly easy.15,16 Therefore, in this article,
(9) (a) Ramachandran, P. V., Ed. Asymmetric Fluoroorganic Chemistry;
ACS Symp. Ser. No. 746; American Chemical Society: Washington, DC,
2000. (b) Soloshonok, V. A., Ed. Enantiocontrolled Synthesis of Fluoro-
Organic Compounds; John Wiley & Sons: New York, 1999.
(10) (a) Yamazaki, T.; Hiraoka, S.; Kitazume, T. Tetrahedron: Asymmetry
1997, 8, 1157. (b) Hiraoka, S.; Yamazaki, T.; Kitazume, T. Synlett 1997,
669.
(11) (a) Yamazaki, T.; Ueki, H.; Kitazume, T. Chem. Commun. 2002,
2670. (b) Ueki, H.; Chiba, T.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
2004, 69, 7616.
(12) Ueki, H.; Chiba, T.; Yamazaki, T.; Kitazume, T. Tetrahedron 2005,
61, 11141.
(13) (a) Ueki, H.; Kitazume, T. J. Org. Chem. 2005, 70, 9354. (b) Ueki,
H.; Kitazume, T. Tetrahedron Lett. 2005, 46, 5439.
(14) Ueki, H.; Chiba, T.; Kitazume, T. Org. Lett. 2005, 7, 1367.
(15) Preparations of them by Wittig-type olefination sometimes encounter
serious disadvantage in terms of olefinic stereochemistry. See: Dolence, J.
M.; Poulter, C. D. Tetrahedron 1996, 52, 119.
(17) (a) Lim, M. H.; Kim, H. O.; Moon, H. R.; Lee, S. J.; Chun, M. W.;
Gao, Z.-G.; Melman, N.; Jacobson, K. A.; Kim, J. H.; Jeong, L. S. Bioorg.
Med. Chem. Lett. 2003, 13, 817. (b) Bruns, S.; Haufe, G. J. Fluorine Chem.
2000, 104, 247. (c) Ichihara, J.; Hanafusa, T. J. Chem. Soc., Chem. Commun.
1989, 1848. (d) Yang, S. S.; Min, J. M.; Beattie, T. R. Synth. Commun.
1988, 18, 899.
(16) In the preparation of them by a transition metal catalyzed cross-
coupling reaction, the olefinic stereochemistries were excellent, but in some
cases the regioselectivity is not perfect, moreover, quite a few examples of
difluoromethylated olefins are described. See: (a) Konno, T.; Chae, J.;
Tanaka, T.; Ishihara, T.; Yamanaka, H. Chem. Commun. 2004, 690. (b)
Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002,
67, 1768.
(18) Tamura, M.; Shibakami, M.; Sekiya, A. J. Fluorine Chem. 1997,
85, 147.
(19) Ishikawa, N.; Takaoka, A.; Iwakiri, H.; Kubota, S.; Kagaruki, S.
R. F. Chem. Lett. 1980, 1107.
(20) Selective SN2′ reactions of gem-difluoroallylic alcohols by DAST
were reported, see: Tellier, F.; Sauveˆtre, R. J. Fluorine Chem. 1993, 62,
183.
J. Org. Chem, Vol. 71, No. 9, 2006 3507

Ueki et al.
SCHEME 2
FIGURE 2.
SCHEME 3
TABLE 2. Stereoselective SN2′ Fluorination of 1a
entry
1
isolated yield (%)
product
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
95
2a
2b
2c
2d
2e
90b
67
64c
91
d
90e
>99
88
2g
2h
2i
would react at the most electrophilic reaction site terminal-
fluorine-attached carbon selectively. With respect to the ole-
finic stereochemistry, Int-A would afford the E-allylic alco-
hols whereas the corresponding Z isomers could be formed from
Int-B; therefore, taking into account the results from the
application of 1b and 1g (Table 2, entries 2 and 7), the steric
repulsions present in Int-A and -B would determine olefinic
stereochemistry of the products.
10
11
1j
1k
64
53
2c
2k
a E/Z ratios were determined by 19F NMR. b E/Z ) 72/28. c Low yield
was attained because of a high volatility of the product. d Complex mixture.
e E/Z ) 71/29.
Next, to explore the scope and limitation of this selective
SN2′ type fluorination, other gem-difluorinated vinyloxiranes
were applied to the standard conditions. All examples listed in
Table 2, except for 1f, demonstrated the selective SN2′ fluorina-
tion with high stereoselectivity; the olefinic stereochemistry was
determined by the NOESY spectroscopy of 2c. However, this
methodology has some limitations as listed below. In the R2
substituted cases (entries 2 and 7), poor olefinic stereoselec-
tivities were observed, and some byproducts were formed when
both epoxide carbons were activated by the adjacent sp2 sys-
tem presumably due to accompanying regiorandom reactions
and/or rearrangements (entries 3, 10, and 11).
To understand the role of fluorine atoms in this selective
fluorination, the corresponding nonfluorinated prototype of 1a
was applied to the standard conditions (Scheme 3). Interestingly,
the treatment of 4 with HF-Py did not result in fluorination,
but the formation of 5 was observed as a sole product by way
of an intramolecular Friedel-Crafts reaction, implying HF was
only playing a role as an acid to activate the substrate in this
case. This unexpected reaction outcome could be rationalized
by the presence or absence of the extraordinarily high electro-
philicity at the terminal sp2 carbon in Int-A and -B introduced
by the fluorine atoms (Figure 2). The 6-exo-tet cyclization would
occur because of delocalization of the positive charge in the
case of 4. It should be mentioned that the corresponding di-
fluorinated intramolecular Friedel-Crafts product 6 was ob-
tained selectively by a completely different method,13a clearly
indicating that fluorine substitutions significantly altered the
compounds’ chemical properties.
The proposed reaction mechanism is depicted in Figure 2.
At the first stage, a proton could activate the substrate strongly,
weakening the allylic epoxide C-O bond and producing
intermediates Int-A or -B.22a Then, the hard fluoride nucleophile
(21) (a) Shenderovich, I. G.; Tolstoy, P. M.; Golubev, N. S.; Smirnov,
S. N.; Denisov, G. S.; Limbach, H.-H. J. Am. Chem. Soc. 2003, 125, 11710.
(b) Yoneda, N. Tetrahedron 1991, 47, 5329. (c) Olah, G. A.; Welch, J. T.;
Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. J. Org. Chem. 1979,
44, 3872.
(22) (a) Aroua, L.; Hedhli, A.; Baklouti, A. Synthesis 1999, 85. (b)
Shimizu, M.; Nakahara, Y. J. Fluorine Chem. 1999, 99, 95. (c) Skupin, R.;
Haufe, G. J. Fluorine Chem. 1998, 92, 157. (d) Sattler, A.; Haufe, G. J.
Fluorine Chem. 1994, 185. (e) Umezawa, J.; Takahashi, O.; Furuhashi, K.;
Nohira, H. Tetrahedron: Asymmetry 1993, 4, 2053. (f) Suga, H.; Hamatani,
T.; Schlosser, M. Tetrahedron 1990, 46, 4247. (g) Muehlbacher, M.; Poulter,
D. J. Org. Chem. 1988, 53, 1026. (h) Alvernhe, G.; Laurent, A.; Haufe, G.
J. Fluorine Chem. 1986, 34, 147. (i) Olah, G. A.; Meidar, D. Isr. J. Chem.
1978, 17, 148.
Selective SN2′ Reductions of gem-Difluorinated Vinylox-
irane. Here the reductions of nonfluorinated vinyloxiranes are
systematically investigated by using several reducing reagents:
LiAlH4,24 DIBAL-H (diisobutylaluminum hydride),24e,25 boron
reagents,26 Pd/RCOOH,27 and others.28 From the preliminary
(24) (a) Vanker, P. S.; Bhattacharya, I.; Vanker, Y. D. Tetrahedron:
Asymmetry 1996, 7, 1683. (b) Parish, E. J.; Schroepfer, G. J., Jr. Tetrahedron
Lett. 1976, 3775. (c) Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins,
R. J.; Arrington, J. P. J. Org. Chem. 1968, 33, 423. (d) Trevoy, L. W.;
Brown, W. G. J. Am. Chem. Soc. 1949, 71, 1675. (e) Lenox, R. S.;
Katzenellenbogen, J. A. J. Am. Chem. Soc. 1973, 95, 957.
(23) Amine-HF are known to react with nonfluorinated vinyloxiranes to
afford Vic-fluorohydrines, see: (a) Hedhli, A.; Baklouti, A. J. Fluorine
Chem. 1995, 70, 141. (b) Robinson, C. Y.; John, V. J. Fluorine Chem.
1993, 62, 283. (c) Bowles, S.; Campbell, M. M.; Sainsbury, M. Tetrahedron
Lett. 1989, 30, 3711.
(25) (a) Takayama, H.; Arai, M.; Kitajima, M.; Aimi, N. Chem. Pharm.
Bull. 2002, 50, 1141. (b) Bloodworth, A. J.; Curtis, R. J.; Spencer, M. D.;
Tallant, N. A. Tetrahedron 1993, 49, 2729. (c) Fronza, G.; Fuganti, C.;
Ho¨gberg, H.-E.; Pedrocchi-Fantoni, G.; Servi, S. Chem. Lett. 1988, 385.
(d) Lee, E.; Paik, Y. H.; Park, S. K. Tetrahedron Lett. 1982, 23, 2671.
3508 J. Org. Chem., Vol. 71, No. 9, 2006

SN2′ Reaction, Fluorination, Reduction
TABLE 3. Reduction of 1 with DIBAL-Ha
TABLE 4. Stereoselective SN2′ Reduction of 1 with BH3‚THFa
entry
1
yield (%)
recovery (%)
yield (%)
recovery
(%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
95: 7a
85: 7b
71: 7c
23:b 7d
77:c 7e
85: 7f
89: 7g
trace
0
0
13
45
17
7
0
88
0
entry
1
solvent
1a n-hexane (64): 7a (<1)
CH2Cl2 77 (<1)
1b n-hexane (47): 7b (<1)
CH2Cl2 (31) (<1)
1c n-hexane (39): 7c (14): 8c
7
8
E/Z of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
>99/<1
>99/<1
65/35
86/15
>99/<1
>99/<1
b
b
0
0
0
0
0
0
7
0
0
0
28
0
7
0
0
0
CH2Cl2
1d n-hexane
CH2Cl2
1e CH2Cl2
1f CH2Cl2
62
(6)
59c (96): 8d
41c (86)
75: 7i
13:d,e 7c
91: 7k
10
11
1j
1k
87
0
75: 7e
(33): 7f
1g n-hexane (16): 7g
>99/<1
45/55
69/31
a E/Z ratios and recoveries were determined by 19F NMR. b E isomer.
c E/Z)13/87. d E/Z)23/77. e Determined by 19F NMR.
CH2Cl2
(21)
1h CH2Cl2
complex mixture
81: 8i
87: 8c
1i
1j n-hexane (2): 7c
CH2Cl2 (4)
1k n-hexane 66: 7k
CH2Cl2 66
n-hexane (<1)
SCHEME 4
>99/<1
>99/<1
92/8
(79)
92/8
a Yields in parentheses, ratios, and recoveries were determined by 19F
NMR. b The remaining 1a decomposed during workup. c Low isolated yield
was attained because of a high volatility of the product.
results of screening (see the Supporting Information), the
selective SN2′ reduction of 1a was realized by using DIBAL-H
to prepare difluorinated E-allylic alcohols, while BH3‚THF
furnished Z-allylic alcohols exclusively.14
Thus, various kinds of gem-difluorinated vinyloxiranes 1a-k
were treated with DIBAL-H under the standard conditions
(Table 3). The site selectivity of the reduction, by DIBAL-H,
highly depended on the structure and substituents of the
substrate. Besides 1a, selective SN2′ reactions with excellent E
selectivity were realized in the case of 1c, 1e, and 1k (entries
5, 6, 9, 17, and 18). When applied to the R2 substituted substrates
1b and 1g (entries 3, 4, 11, and 12), the yield and olefinic
stereoselectivity decreased presumably due to steric effects.
Stereoisomeric 1c and 1j were found to exhibit a remarkable
regioselective difference: the former E-oxirane demonstrating
the SN2′ selectivity whereas the SN2 product 8 was formed
selectively in the latter Z-oxirane case (entries 5, 6, 15, and
16). This unexpected SN2 selectivity was also observed when
1d and 1i were used as a substrate (entries 7, 8, and 14).
Next, to investigate the generality of the reaction with
BH3‚THF, gem-difluorinated vinyloxiranes were applied to the
standard conditions (Table 4). The Z selective SN2′ reaction was
realized in almost all examples except for the substrate pos-
sessing the substituents at the R4 moiety (entries 4, 8, and 10).
The olefinic stereochemistry was determined by the analysis
of NOESY spectrums of 7a, 7c, and 7k cases, indicating that
DIBAL-H attained the E isomer of 7 selectively while the
corresponding Z isomer was formed from the reaction with BH3‚
THF.
To account for the current olefinic stereochemical outcome
of 7a-k from the reduction of 1a-k with DIBAL-H and
BH3‚THF, a plausible reaction mechanism of them is described
in Scheme 4. DIBAL-H and BH3 could activate the oxirane
moiety strongly leading to an intramolecular hydride shift to
the fluorine-attached-terminal carbon. The E isomer would be
furnished from the s-trans conformer by way of Int-C, while
Int-D could be generated from the s-cis conformer to afford
the Z isomer. The chair-like six-membered-ring conformation
of Int-D would be favorable in the case of reducing reagents
with relatively small ligands (L) such as BH3‚THF producing
the Z product easily. On the other hand, in the case of DIBAL-H
whose L are relatively large, steric repulsion between the L and
(26) (a) Hu, S.; Jayaraman, S.; Oehlschlager, A. C. J. Org. Chem. 1999,
64, 3719. (b) Zaildwich, M.; Krzeminski, M. Tetrahedron Lett. 1996, 37,
7131. (c) Zaildwich, M.; Uzarewich, A.; Sarnowski, R. Synthesis 1979,
62.
(27) (a) Noguchi, Y.; Yamada, T.; Uchiro, H.; Kobayashi, S. Tetrahedron
Lett. 2000, 41, 7493. (b) David, H.; Dupuis, L.; Guillerez, M.-G.; Guibe´,
F. Tetrahedron Lett. 2000, 41, 3335. (c) Trost, B. M.; McEachern, E. J. J.
Am. Chem. Soc. 1999, 121, 8649. (d) Oshima, M.; Yamazaki, H.; Shimizu,
I.; Nisar, M.; Tsuji, J. J. Am. Chem. Soc. 1989, 111, 6280. (e) Shimizu, I.;
Oshima, M.; Nisar, M.; Tsuji, J. Chem. Lett. 1986, 1775. (f) Deardorff, D.
R.; Myles, D. C.; MacFerrin, K. D. Tetrahedron Lett. 1985, 26, 5615. (g)
Tsuji, J.; Shimizu, I.; Minami, I. Chem. Lett. 1984, 1017.
(28) (a) Gupta, A.; Vanker, Y. D. Tetrahedron Lett. 1999, 40, 1369. (b)
Aurrecoechea, J. M.; Iztueta, E. Tetrahedron Lett. 1995, 36, 7129. (c)
Molander, G. A.; La Belle, B. E.; Hahn, G. J. Org. Chem. 1986, 51, 5259.
J. Org. Chem, Vol. 71, No. 9, 2006 3509

Ueki et al.
SCHEME 5
and the inherent low stability, independent reductions of the
monofluorinated vinyloxirane 11 by DIBAL-H and BH3‚THF
were performed under the standard conditions. However, to our
disappointment, both reactions resulted in a complex mixture,
and we could not obtain the desired monofluoromethylated
allylic alcohol (see the Supporting Information). From the
obtained results, it was proved that two fluorine atom substitu-
tions on an olefin moiety are crucial for the selective SN2′
reductions.
Conclusion
In summary, gem-difluorinated vinyloxiranes 1 were dem-
onstrated as useful synthetic intermediates for the preparation
of tri- and difluoromethylated olefins utilizing their selective
SN2′ fluorination and reductions. HF-Py worked effectively for
fluorine introduction to gem-difluorinated vinyloxiranes at the
terminal-fluorine-attached carbon to afford trifluoromethylated
allylic alcohols in the E form exclusively. Their reductions with
DIBAL-H led to the selective formation of E-difluoromethylated
olefins whereas the corresponding Z isomers were obtained
exclusively by BH3‚THF. Compared with the results from mono-
and nonfluorinated vinyloxiranes, the highly regio- and stereo-
control could be attributed to the alternating properties by the
two fluorine atoms on the olefin moiety. These highly selective
SN2′ reactions allowed an access to various geometrically
controlled alkenes with a tri- or difluoromethyl group.
the epoxide moiety in Int-D could inhibit the reaction pathway
to the Z product therefore leading to the formation of the E
isomer.
The corresponding nonfluorinated prototype of 1a was
reduced under the standard selective SN2′ reductions as a
comparison (Scheme 5). To our surprise, no SN2′ product was
obtained by DIBAL-H, instead a homoallylic alcohol 10 was
formed selectively, while high SN2′ selectivity was observed in
the fluorinated case (see, Table 3, entry 2). This difference in
regioselectivity based on the degree of fluorine could be
attributed to the positive charge on the reaction sites: the
terminal sp2 carbon of gem-difluorinated vinyloxiranes possesses
the most electropositive charge due to the strong electronic
repulsion between lone pairs of fluorine atoms and π-electrons,11b
whereas the allylic epoxide carbon would be expected to be
the most electropositive in the case of the nonfluorinated
prototype. In other words, the site selectivity of the reduction
with DIBAL-H would be determined by the positive charges
on the carbons if a substrate has small steric encumbrance. On
the other hand, the reduction of 4 with BH3‚THF resulted in a
complex mixture while Z-7 was obtained exclusively in the
fluorinated case (see, Table 4, entry 1). These different
experimental results could be explained by the computational
results.11b These results indicate that the HOMO of gem-
difluorinated vinyloxiranes lies on the epoxide oxygen atom
whereas it is on the olefin moiety in the nonfluorinated case.
In the former case BH3 can activate the epoxide moiety to
produce Int-D smoothly, while such side reactions as hydrobo-
ration would occur easily to retard the SN2′ selectivity in the
latter case.
As described above, we have established the regio- and
stereoselective synthetic methods for tri- and difluoromethylated
olefins from gem-difluorinated vinyloxiranes. Then, our attention
was turned to the preparation of monofluorinated olefins from
the same key intermediate gem-difluorinated vinyloxirane.
Following the strategy depicted in Scheme 1, we decided to
investigate a selective reduction from gem-difluoro olefins to
the corresponding monofluorinated ones. However, the attempt
by LiAlH429 or Red-Al (bis(2-methoxyethoxy)aluminum dihy-
dride)30 was not successful. After an extensive study, we found
an alternative method to prepare monofluorinated vinyloxirane
11 (see the Supporting Information). Although the isolated 11
is not a useful synthetic intermediate because of the low yield
Experimental Sections
General Procedure for the Fluorination of 1 with HF-Py. The
reaction of 1a is described as a representative example. HF-Py
(0.022 mL, 0.89 mmol) was added to a flask containing 1a (0.10
g, 0.45 mmol) in 5 mL of CH2Cl2 at 0 °C under Ar atmosphere
and the reaction mixture was stirred for 1 h. Then, the reaction
was quenched with H2O and the organic layer was extracted with
Et2O three times and dried over anhydrous MgSO4. Removal of
the solvents and purification with slica gel column chromatography
(n-hexane:AcOEt ) 4:1) furnished the pure desired 2a in 91%.
(E)-1-Phenyl-5-trifluoromethylhex-4-en-3-ol (2a): 1H NMR δ
1.75 (3 H, d, J ) 1.10 Hz), 1.82 (1 H, dddd, J ) 14.5, 9.07, 6.87,
5.22 Hz), 1.98 (1 H, dddd, J ) 14.0, 8.79, 7.68, 6.32 Hz), 2.68 (1
H, ddd, J ) 14.0, 8.79, 6.87 Hz), 2.75 (1 H, ddd, J ) 14.0, 9.07,
6.32 Hz), 4.42 (1 H, m), 6.07 (1 H, dddd, J ) 8.52, 3.02, 3.02,
1.37 Hz), 7.16-7.34 (5 H, m). 19F NMR δ 91.7 (s). 13C NMR δ
11.0 (dd, J ) 2.57, 1.43 Hz), 31.3, 38.1 (dd, J ) 4.01, 2.86 Hz),
67.0, 123.7 (q, J ) 272.9 Hz), 126.0, 126.4 (q, J ) 24.5 Hz), 128.2,
128.3, 134.7 (dd, J ) 11.0, 5.44 Hz), 140.9. IR (neat) ν 670, 747,
892, 1030, 1118, 1177, 1335, 1455, 1496, 2863, 2933, 3029, 3064,
3375. Anal. Calcd for C13H15F3O: C, 63.93; H, 6.19. Found: C,
63.97; H, 6.05.
Typical Procedure for the Reduction of 1 with DIBAL-H.
The reaction of (E)-3,4-epoxy-1,1-difluoro-2-methyl-6-phenylhex-
1-ene 1a in CH2Cl2 is described as a representative example. To a
solution of 1a (0.10 g, 0.45 mmol) in 5 mL of dry CH2Cl2 was
added 2.0 equiv of DIBAL-H (0.89 mmol) at -78 °C under argon.
After 1.0 h of stirring, the reaction was quenched with 3 N HCl
aq, and the organic layer was extracted with CH2Cl2 three times
and dried over anhydrous MgSO4. Removal of the solvents and
purification with silica gel column chromatography (n-hexane:
AcOEt ) 4:1) afforded the pure E-7a in 66% yield.
(29) (a) Frohn, H. J.; Bardin, V. V. J. Fluorine Chem. 2003, 123, 43.
(b) Huang, X.-H.; He, P.-Y.; Shi, G.-Q. J. Org. Chem. 2000, 65, 627. (c)
Tellier, F.; Sauveˆtre, R. J. Fluorine Chem. 1996, 76, 181. (d) Tellier, F.;
Sauveˆtre, R. Tetrahedron Lett. 1995, 36, 4223. (e) Tellier, F.; Sauveˆtre,
R.; Normant, J.-F Tetrahedron Lett. 1987, 28, 3335. (f) Suda, M.
Tetrahedron Lett. 1981, 22, 1421.
Typical Procedure for the Reduction of 1 with BH3‚THF.
The reaction of (E)-3,4-epoxy-1,1-difluoro-2-methyl-6-phenylhex-
1-ene 1a is described as a representative example. To a solution of
1a (0.10 g, 0.45 mmol) in 5 mL of dry THF was added 0.75 equiv
of BH3‚THF THF solution (0.33 mmol) under argon. After 1.0 h
of stirring at room temperature, the reaction was quenched with 3
(30) Hayashi, S.; Nakai, T.; Ishikawa, N. Chem. Lett. 1979, 983.
3510 J. Org. Chem., Vol. 71, No. 9, 2006

SN2′ Reaction, Fluorination, Reduction
N NaOH aq, and the organic layer was extracted with Et2O three
times, washed with brine, and dried over anhydrous MgSO4.
Removal of the solvents and purification with silica gel column
chromatography (n-hexane:AcOEt ) 4:1) afforded the pure Z-7a
in 95% yield.
10.0, 9.73 Hz), 141.1. Z isomer: 1H NMR δ 1.81 (1 H, dddd, J )
12.7, 9.15, 6.96, 5.83 Hz), 1.83 (3 H, m), 1.95 (1 H, dddd, J )
13.7, 8.91, 7.32, 6.38 Hz), 2.67 (1 H, ddd, J ) 13.9, 8.91, 6.96
Hz), 2.70 (1 H, ddd, J ) 14.0, 9.16, 6.47 Hz), 4.44 (1 H, m), 5.63
(1 H, m), 6.42 (1 H, t, J ) 55.7 Hz), 7.16-7.32 (5 H, m). 19F
NMR δ 44.8 (d, J ) 55.6 Hz). 13C NMR δ 15.7 (t, J ) 3.01 Hz),
31.4, 38.9 (t, J ) 1.14 Hz), 66.5 (t, J ) 0.86 Hz), 112.0 (t, J )
233.9 Hz), 125.9, 128.2, 128.3, 131.2 (t, J ) 22.5 Hz), 136.3 (t, J
) 8.88 Hz), 141.0.
6,6-Difluoro-5-methyl-1-phenylhex-4-en-3-ol (7a): IR (neat)
ν 509, 698, 748, 822, 841, 883, 918, 1018, 1092, 1153, 1207, 1339,
1362, 1396, 1454, 1497, 1524, 1585, 1605, 1655, 1674, 1686, 1717,
1751, 1802, 1871, 1948, 2862, 2928, 3028, 3063, 3086, 3368, 3530,
3568, 3588 cm-1. Anal. Calcd for C13H16F2O: C, 69.01; H, 7.13.
Found: C, 69.28; H, 6.92. E isomer: 1H NMR δ 1.71 (3 H, dd, J
) 1.48, 0.38 Hz), 1.80 (1 H, dddd, J ) 13.7, 9.61, 6.87, 5.77 Hz),
1.95 (1 H, dddd, J ) 13.7, 8.79, 7.42, 6.32 Hz), 2.67 (1 H, ddd, J
) 13.7, 8.79, 6.60 Hz), 2.74 (1 H, ddd, J ) 14.0, 9.34, 6.32 Hz),
4.44 (1 H, m), 5.74 (1 H, m), 5.92 (1 H, t, J ) 56.2 Hz), 7.10-
7.35 (5 H, m). 19F NMR δ 45.8 (1 F, dd, J ) 299.0, 56.0 Hz), 46.9
(1 F, dd, J ) 299.0, 56.0 Hz). 13C NMR δ 9.66 (dd, J ) 2.29, 2.01
Hz), 31.4, 38.3 (t, J ) 1.72 Hz), 67.0, 117.1 (t, J ) 236.8 Hz),
125.9, 128.2, 128.3, 131.1 (dd, J ) 21.8, 21.5 Hz), 135.2 (dd, J )
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, reduction of 1a with
various reducing reagents (Table 5), reaction of 1a with DIBAL-H
(Table 6), reaction of 1a with BH3‚THF (Table 7), 1H NMR spectra
of E-2a, E-7a, and Z-7a. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060089C
J. Org. Chem, Vol. 71, No. 9, 2006 3511