Facile synthesis of fluoroalkenes by palladium-catalyzed reductive defluorination of allylic gem-difluorides

Article abstract of DOI:10.1021/ol701627v

Chemo- and stereoselective synthesis of fluoroalkenes was achieved in excellent yields via Pd-catalyzed C-F bond activation. In this transformation, Et₃N plays a crucial role to produce reactive hydride species such as Ph(EtO)SiH₂ an

Full text of DOI:10.1021/ol701627v

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3465-3468
Facile Synthesis of Fluoroalkenes by
Palladium-Catalyzed Reductive
Defluorination of Allylic gem-Difluorides
Tetsuo Narumi, Kenji Tomita, Eriko Inokuchi, Kazuya Kobayashi, Shinya Oishi,
Hiroaki Ohno, and Nobutaka Fujii*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
nfujii@pharm.kyoto-u.ac.jp
Received July 13, 2007
ABSTRACT
Chemo- and stereoselective synthesis of fluoroalkenes was achieved in excellent yields via Pd-catalyzed C
−F bond activation. In this
transformation, Et3N plays a crucial role to produce reactive hydride species such as Ph(EtO)SiH2 and Ph(EtO)2SiH by promoting dehydrogenative
coupling. The reaction proceeds efficiently at 50
peptidomimetics.
°C with a variety of substrates and is also useful for the synthesis of fluoroalkene
Although the development of catalytic reactions involving
C-F bond activation represents a great challenge in organic
chemistry,1 only a few examples of Pd-catalyzed C-F bond
activation have been reported to date.2 Recently, several
groups have disclosed cross-coupling reactions of alkyl or
aryl fluorides through Pd-catalyzed C-F bond activation.3
One example of Pd-catalyzed allylic C-F bond activation
is the hydrogenolysis of allyl fluorides in the presence of
Pd/C,2a which provides a facile method for the replacement
of fluorine by hydrogen atom under mild conditions. A main
drawback of this transformation exists in the chemoselectivity
issue: the reaction always gives a mixture of two products,
one formed by replacement of the fluorine by a hydrogen
atom followed by saturation of the double bond, and the other
resulting from the simple hydrogenation of the double bond.
On the basis of these pioneering works, we envisioned that
the reaction of allylic gem-difluoride 1 with a homogeneous
palladium catalyst in the presence of appropriate additives
having an affinity to fluorine could promote the elimination
of fluorine, leading to the generation of a fluorinated π-allyl
palladium intermediate 2. By a chemoselective reaction with
an appropriate nucleophile, this intermediate is expected to
be transformed to (Z)-fluoroalkene 3,4 which constitutes an
(1) Recent reviews for activation and functionalization of C-F bonds,
see: (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. ReV.
1994, 94, 373-431. (b) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem.
Ber./Recl. 1997, 130, 145-154. (c) Murai, S. ActiVation of UnreactiVe Bonds
and Organic Synthesis; Springer: New York, 1999; pp 243-269. (d)
Hiyama, T. Organofluorine Compounds Chemistry and Applications;
Springer: New York, 2000.
(2) Pd-catalyzed C-F bond activation: (a) Hudlicky, M. J. Fluorine
Chem. 1989, 44, 345-359. (b) Hintermann, L.; La¨ng, F.; Maire, P.; Togni,
A. Eur. J. Inorg. Chem. 2006, 1397-1412. (c) Torrens, H. Coord. Chem.
ReV. 2005, 249, 1957-1985. (d) Ichikawa, J.; Nadano, R.; Ito, N. Chem.
Commun. 2005, 4425-4427.
(3) Pd-catalyzed cross coupling via C-F bond activation: (a) Widdow-
son, D. A.; Wilhelm, R. Chem. Commun. 1999, 2211-2212. (b) Wilhelm,
R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 2000, 3808-3813.
(c) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578-579. (d)
Mi, Kim, Y.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696-1697. (e) Terao,
J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646-
5647.
10.1021/ol701627v CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/27/2007

important class of molecules such as peptide isosteres,5a-d
enzyme inhibitors,5e and liquid-crystalline materials.5f
Therefore, we tested the reaction in the presence of triethyl-
amine instead of sodium dimethyl malonate to obtain 6a in
increased yields (28%).
After screening of the reaction conditions, we were pleased
to find that the combination of dppp and EtOH at 50 °C
afforded the expected products 6a in up to 96% yield (Table
1, entry 1). However, a small amount of undesired diene 7,
Table 1. Effect of the Amount of Et3Na
Figure 1. Synthesis of fluoroalkene via Pd catalysis.
Herein, we present a general catalytic system for the facile
synthesis of fluoroalkene skeleta from readily available allylic
difluorides by Pd-catalyzed reductive defluorination with
phenylsilane. Some insight into the mechanistic aspect of
this transformation is also described.
In an initial study, we investigated the Pd-catalyzed allylic
alkylation6 of γ,γ-difluoro-R,â-enoate 4a, which can be
readily prepared from isobutyl aldehyde7 by modifying
Honda’s protocol.8 Various additives were screened for the
reaction of enoate 4a with dimethyl sodiomalonate in the
presence of a catalytic amount of [η3-C3H5PdCl]2 (5) and
dppe. Although TMSCl, Et4Si, (EtO)4Si, or Me3Al did not
promote the desired defluorination reaction, we found that,
when using PhSiH3, a small amount of reductive defluori-
nated product 6a was obtained (3%), without forming
alkylated products 6b [X ) CH(CO2Me)2] (Scheme 1). Since
entry
Et3N [equiv]
yield of 6ab [%]
E:Zc
1
2
3
4
5
2.0
1.0
0.5
0.1
0.01
<96
99
99
99
87
20:80
17:83
15:85
9:91
6:94
a Reactions were carried out with 4a (0.13 mmol), PhSiH3 (0.25 mmol),
Et3N, [η3-C3H5PdCl]2 5 (2.5 mol %), and dppp (5.0 mol %) in EtOH (2.5
mL) at 50 °C for 2 h. b Yields of isolated products. c The ratio of E/Z isomer
1
was determined by H NMR spectroscopy.
presumably produced by Et3N-assisted â-hydride elimination
of a plausible intermediate of the type 2, was observed in
an irreproducible fashion (<10%). Therefore, we performed
the reaction with 1.0 equiv of Et3N to obtain the desired
defluorinated products in 99% yield without the formation
of the â-elimination product 7 (entry 2). Unexpectedly, the
reduction of Et3N to a catalytic amount improves the E/Z
selectivity (entries 3-5). Of particular interest is the forma-
tion of a small amount of the bis-defluorinated product 8,
which was obtained in 8% yield when using 1 mol % of
Et3N.9 Finally, the reaction can be conducted in quantitative
conversion at catalyst loadings as low as 0.16 mol % (eq 1).
Scheme 1. Pd-Catalyzed Allylic Alkylation
the reduced product 6a was not detected without using
dimethyl sodiomalonate, we postulated that basicity of
sodium malonate plays an important role in this reaction.
(4) For a recent example of the fluoroalkene synthesis: (a) Yoshida,
M.; Komata, A.; Hara, S. Tetrahedron 2006, 62, 8636-8645 and references
cited therein.
(5) (a) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem.,
Int. Ed. Engl. 2007, 46, 1290-1292. (b) Narumi, T.; Niida, A.; Tomita,
K.; Oishi, S.; Otaka, A.; Ohno, H.; Fujii, N. Chem. Commun. 2006, 4720-
4722. (c) Nakamura, Y.; Okada, M.; Sato, A.; Horikawa, H.; Koura, M.;
Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741-5753. (d) Allmendinger,
T.; Felder, E.; Hungerbu¨hler, E. Tetrahedron Lett. 1990, 31, 7301-7304.
(e) Bey, P.; McCarthy, J. R.; McDonald, I. A. ACS Symp. Ser. 1991, 456,
105-133 and references cited therein. (f) Yokokoji, O.; Shimizu, T.; Kumai,
S. JP 08040952, 1996 [Chem. Abstr. 1996, 124, 316586].
(6) For review, see: (a) Tsuji, J. Palladium Reagents and Catalysis,
InnoVations in Organic Synthesis; Wiley: New York, 1995. (b) Trost, B.
M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422. (c) Johannsen,
M.; Jorgensen, K. A. Chem. ReV. 1998, 98, 1689-1708. (d) Paquin, J.-F.;
Lautens M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany, 2004: Vol.
2, pp 73-95 and references cited therein. (e) Trost, B. M.; Crawley, M. L.
Chem. ReV. 2003, 103, 2921-2943.
With these results in hand, we examined the scope of this
reaction with readily available and synthetically useful
(7) (a) Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe,
H.; Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004,
69, 1634-1645 and references cited therein.
(8) Honda, T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002,
50, 307-308.
(9) Formation of defluorinated product 8 could be rationalized by reaction
of π-allyl Pd intermediate by hydride at the fluorinated carbon to give allyl
fluoride followed by re-reductive defluorination.
3466
Org. Lett., Vol. 9, No. 17, 2007

applicability of this reaction to the substrates without a con-
jugated carbonyl moiety such as benzyl ether 16 and nitrile
18 (entries 9 and 10) clearly demonstrates an advantage of
this reaction over the known related reduction using a single-
electron donor,7a which is limited to R,â-unsaturated carbonyl
compounds.
Table 2. Pd- and Et3N-Catalyzed Reductive Defluorinationa
To gain some insight into the mechanism of this trans-
formation, we examined isotopic labeling experiments (Scheme
2). The reaction with PhSiD3 in EtOH induced deuterium
Scheme 2. Isotopic Labeling Experiments
incorporation at the R-position (97% -d) (eq 2). On the other
hand, the reaction performed in EtO-D with PhSiH3
promoted no deuterium incorporation (eq 3), suggesting that
the introduced hydrogen originates from PhSiH3. Further-
more, to determine the hydride species, we performed the
reaction with PhSiH3, Ph(EtO)SiH2, and Ph(EtO)2SiH in the
absence of Et3N (Table 3). While no reaction was observed
Table 3. Investigation of the Hydride Speciesa
entry
organosilane
yield of 6ab [%]
E:Zc
1
2
3
PhSiH3
Ph(EtO)SiH2
Ph(EtO)2SiH
d
83
70
13:87
45:55
a All reactions were carried out with allylic gem-difluoride (1.0 equiv),
PhSiH3 (2.0 equiv), Et3N (10 mol %), [η3-C3H5PdCl]2 5 (2.5 mol %), and
dppp (5.0 mol %) in EtOH at 50 °C for 2 h. b Yields of isolated prod-
ucts. c The ratio of E/Z isomer was determined by 1H NMR spectros-
copy. d A trace amount of starting material was detected by 1H NMR
spectroscopy.
a Reactions were carried out with 4a (0.13 mmol), organosilane (0.25
mmol), [η3-C3H5PdCl]2 5 (2.5 mol %), and dppp (5.0 mol %) in EtOH (2.5
mL) at 50 °C for 2 h. b Yields of isolated products. c The ratio of E/Z isomers
was determined by H NMR spectroscopy. d No reaction was observed.
1
substrates possessing various functional groups (Table 2).
In all cases, the reaction was completely chemoselective, and
good to excellent yields of fluoroalkenes were obtained with
modest to high selectivity. N-Boc amide, esters, and sub-
stituents such as alkyl and siloxy groups introduced at the
δ-carbon did not affect the reaction (entries 1-3). Further-
more, amides, including a peptide, 11a-c (entries 4-6), (Z)-
enoate 13 (entry 7), and lactam 14 (entry 8), can be employed
to give the desired fluoroalkenes 12a-c, 6c, and 15. The
with PhSiH3 (entry 1), the reactions with Ph(EtO)SiH2 and
Ph(EtO)2SiH proceeded smoothly to provide the desired
defluorinated products 6a (entries 2 and 3). Therefore, these
alkoxysilanes would be considered as the actual reactive
species. On the basis of these results and Buchwald’s
observation,10 Et3N plays a crucial role for the generation
of these active hydride sources such as Ph(EtO)SiH2 and
Ph(EtO)2SiH by promoting catalytic dehydrogenative cou-
pling of PhSiH3 with EtOH.11 Once those active species have
Org. Lett., Vol. 9, No. 17, 2007
3467

been generated, they could work both as reducing agents to
generate Pd0 complexes and as hydride sources.
utilizing Pd-catalyzed reductive defluorination. This is an
unparalleled example of a highly effective catalytic synthesis
of a fluoroalkene skeleton, including peptidomimetics.
Mechanistic study has proven that Et3N promotes the
dehydrogenative coupling of PhSiH3 with EtOH to produce
reactive species.
These results could explain the dependence of the chemical
yield and stereoselectivity on the amount of Et3N in Table
1. A catalytic amount of Et3N would generate the reactive
alkoxysilanes in an appropriate rate through dehydrogenative
coupling, while the excess of Et3N considerably accelerates
this process, which would consume reactive species to cause
undesired side reactions.
Acknowledgment. This research was supported in part
by the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science”, a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, the Japan Society
for the Promotion of Science (JSPS), and the Japan Health
Science Foundation.
In summary, we have developed a novel general method
for the synthesis of fluoroalkenes under mild conditions
(10) Involvement of alkoxysilane accounts for the titanium-catalyzed
hydrosilylation of imine with PhSiH3, see: Verdaguer, X.; Lange, U. E.
W.; Reding, M. T.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 6784-
6785.
(11) For examples of base-catalyzed dehydrogenative coupling of silanes
with alcohols, see: (a) Lukevics, E.; Dzintara, M. J. Organomet. Chem.
1984, 271, 307-317. (b) Gilman, H.; Dunn, G. H.; Hartzfeld, H.; Smith,
A. G. J. Am. Chem. Soc. 1955, 77, 1287-1288. (c) Bazant, V.; Chvalovsky,
V.; Rathousky J. In Organosilicon Compounds; Publishing House of the
Czechoslovak Academy of Science: Prague, Czechoslovakia, 1965: pp 54-
56.
Supporting Information Available: Representative pro-
cedures and spectral and analytical data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL701627V
3468
Org. Lett., Vol. 9, No. 17, 2007