A new sequential defluorination route to α-fluoro-α,β-unsaturated ketones from trifluoromethyl ketones

Article abstract of DOI:10.1016/S0040-4039(02)01343-6

α-Fluoro-α,β-unsaturated ketones were prepared from trifluoromethyl ketones via a sequence involving Mg metal promoted successive double defluorination. Trifluoromethyl ketones were transformed to β,β-difluoroenol silyl ethers which were then coupled with

Full text of DOI:10.1016/S0040-4039(02)01343-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6099–6102
A new sequential defluorination route to a-fluoro-a,b-unsaturated
ketones from trifluoromethyl ketones
Hiroshi Hata,a Takeshi Kobayashi,a Hideki Amii,a Kenji Uneyamaa,* and John T. Welchb,*
aDepartment of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
bDepartment of Chemistry, The University at Albany, State University of New York, Albany, NY 12222, USA
Received 15 June 2002; revised 1 July 2002; accepted 4 July 2002
Abstract—a-Fluoro-a,b-unsaturated ketones were prepared from trifluoromethyl ketones via a sequence involving Mg metal
promoted successive double defluorination. Trifluoromethyl ketones were transformed to b,b-difluoroenol silyl ethers which were
then coupled with aldehydes and ketones to b-hydroxy-a,a-difluoroketones. A second Mg-promoted defluorination of the
hydroxyketones followed by acid-catalyzed hydrolysis of g-hydroxy-b-fluoroenol silyl ethers provided a-fluoro-a,b-unsaturated
ketones as a final product. © 2002 Elsevier Science Ltd. All rights reserved.
Peptides have been modified to improve their biological
activities by changing the backbone structure.1 Replace-
ment of the amide bond with a monofluorinated car-
bon–carbon double bond (CFꢀC) has been recognized
to provide conformationally fixed peptide bond
isosteres (Scheme 1).2,3 Physical data such as bond
length, dipole moment, and charge distribution of
fluoroolefins also suggest the similarity between an
amide moiety and a fluoroolefin.4 On this basis, several
peptide mimetics possessing monofluoroolefinic skele-
tons have been prepared.2,3,5 a-Fluoro-a,b-unsaturated
carbonyl compounds are promising precursors for
fluoroalkene oligopeptide isosteres, and have been pre-
pared by a variety of approaches such as aldol reaction
of a-fluoro-a-silylacetates with ketones followed by
Peterson olefination,3b alkylation of 1,1,1,2-tetra-
fluoroethane with aldehydes followed by acid-catalyzed
hydrolysis,6 Grignard reaction of b-fluorovinamidium
salt,7 Wittig–Horner reaction with diethylphosphono-2-
fluoroacetate,8 Pd-catalyzed carbonylation of 1-
fluorovinyl-stannanes,9 and so on.10
To further define the biological utility of the peptide
mimetics, it is necessary to develop a more effective
route for the synthesis of a-fluoro-a,b-unsaturated car-
bonyl compounds, promising intermediates for
fluoroalkene oligopeptide isosteres. Recently, we
reported Mg(0)-promoted defluorinative silylenolization
of trifluoromethyl ketones,11 which might be applicable
to the construction of b-hydroxy-a,a-difluorocarbonyl
compounds due to the readily reducibility of multi-
fluoromethyl carbonyl compounds with metallic magne-
sium. This communication describes a double defluori-
nation pathway leading to an efficient synthesis of
a-fluoro-a,b-unsaturated carbonyl compounds.
The first CꢁF bond cleavage in the sequence for
monofluoroolefins is Mg(0)-promoted selective defluori-
native silylation of trifluoromethylketones 1 to afford
2,2-difluoroenol silyl ethers 2.11 Without further purifi-
cation, the crude enols 2 were employed directly in the
next aldol reaction. The TiCl4-catalyzed aldol reaction
of 2 with various aldehydes and ketones gave 3 in good
overall yields (from 1). The results of transformation of
1 to 3 are summarized in Scheme 2.
Scheme 1.
Keywords: fluorine and compounds; magnesium; cleavage reaction;
aldols; enones.
* Corresponding authors. Tel.: +81-(0)86-251-8075; fax: +81-(0)86-
251-8021; e-mail: uneyamak@cc.okayama-u.ac.jp
The second CꢁF bond cleavage for the synthesis of the
monofluoroolefins requires defluorinative silylation of
the difluoroaldols 3 to give monofluoroenol silyl ethers
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01343-6

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H. Hata et al. / Tetrahedron Letters 43 (2002) 6099–6102
Scheme 2.
4. Upon treatment of 3a with Mg metal (8 equiv.) and
Me3SiCl (4 equiv.) in THF at 0°C, the defluorinative
silylation completed within 30 min affording
monofluoroenol silyl ether 4a. It is noted that the
defluorination reaction proceeded smoothly with no
need for precautionary protection of the hydroxyl
group in 3a. After simple filtration and treatment of the
crude enol 4a with aq. HCl, a-fluoro-a,b-unsaturated
ketone 5a was obtained in 72% yield from 3a.
tones 3e and 3f from cyclic ketones underwent defluori-
nation cleanly, affording exo-fluoromethylene cyclic
compounds 5e and 5f in 74% and 82% yields, respec-
tively. However, the reaction of 3g (obtained from
acetophenone) provided a complex mixture under the
same experimental conditions. When O-silylated
derivative 3h was subjected to the Mg-promoted
defluorination and subsequent hydrolysis, the desired
enone 5g was formed as a mixture (E/Z=1:4) of
stereoisomers in 74% yield.13
In light of operational simplicity and high efficiency,
Mg-promoted selective defluorination of 3 and subse-
quent hydrolysis of 4 gave a reliable route for preparing
monofluoro enones 5.12
Furthermore, a-fluoro-a,b-unsaturated ester
8 was
obtained by the following Baeyer–Villiger oxidation
procedures (Scheme 4). a-Fluoro-b-hydroxy-b-phenyl
(p-methoxyphenyl) ketone (7) which was prepared from
6 by Mg-promoted defluorination followed by a basic
hydrolysis (route A), and which was also prepared from
difluoromethyl ketone 9 by Mg-promoted CꢁF bond
cleavage14 followed by aldol reaction with benzaldehyde
(route B), could be transformed to (Z)-a-fluorocinna-
mate 8 in reasonable yield.
As shown in Scheme 3, this procedure worked well for
other b-hydroxyketones 3b–d derived from aldehydes to
provide 5b–d in good yields. Interestingly, in both the
case of 3a–c (from aromatic aldehydes; R1=Ar) and 3d
(from an aliphatic aldehyde; R1=C5H11), the reactions
led to exclusive formation of (Z)-5a–d.13 b-Hydroxyke-
Scheme 3.

H. Hata et al. / Tetrahedron Letters 43 (2002) 6099–6102
6101
Scheme 4.
5. (a) Otaka, A.; Mitsuyama, E.; Watanabe, H.; Tama-
mura, H.; Fujii, N. Chem. Commun. 2000, 1081; (b)
Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.;
Tamamura, H.; Fujii, H. Tetrahedron Lett. 2001, 42,
5443.
6. Kanai, M.; Percy, J. M. Tetrahedron Lett. 2000, 41,
2453.
7. Yamanaka, H.; Odani, Y.; Ishihara, T.; Gupton, J. T.
Tetrahedron Lett. 1998, 39, 6947.
8. (a) Kim, B. T.; Min, Y. K.; Asami, T.; Park, N. K.;
Kwon, O. Y.; Cho, K. Y.; Yoshida, S. Tetrahedron
Lett. 1997, 38, 1797; (b) Komatsu, Y.; Kitazume, T. J.
Fluorine Chem. 1998, 87, 101.
Compared with published methods, the present
defluorination route to a-fluoro-a,b-unsaturated
ketones has several advantages. The procedure for
selective defluorination is very simple; Mg metal as a
reducing agent is inexpensive and easily handled.14 Sim-
ple repetition of the defluorination procedures allowed
selective formation of the monofluorinated enones, with
high stereoselectivities in some cases. Trifluoromethyl
ketones were successfully transformed to a-fluoro-a,b-
unsaturated esters without the necessity to employ toxic
monofluoroacetates as a starting material. Thus, the
design of the reaction sequences involving CꢁF bond
cleavage enables the development of various practical
transformations, with potential biological and chemical
utility.
9. Chen, C.; Wilcoxen, K.; Kim, K.-I.; MaCarthy, J. R.
Tetrahedron Lett. 1997, 38, 7677.
10. (a) Ring-opening of a,b-epoxyketone with Et3N/3HF:
Todoroki, Y.; Hirai, N.; Ohigashi, H. Tetrahedron
1995, 51, 6911; (b) Fluoroolefination of b-ketoesters
with DAST: Bildstein, S.; Ducep, J.-B.; Jacobi, D.;
Zimmermann, P. Tetrahedron Lett. 1995, 36, 5007; (c)
O-Acetylation of a-fluoromalonaldehyde: Funabiki, K.;
Fukushima, Y.; Matsui, M.; Shibata, K. J. Org. Chem.
2000, 65, 606; (d) Electrochemical fluorination of b-
phenylsulfenyl-a,b-unsaturated ketones: Andres, D. F.;
Dietrich, U.; Laurent, E. G.; Marquet, B. S. Tetra-
hedron 1997, 53, 647.
Acknowledgements
The authors are grateful to the Ministry of Education,
Science, Culture, Sport, and Technology of Japan (No.
13555254 and 12450356) for financial support and SC-
NMR laboratory of Okayama University for 19F NMR
analysis.
11. Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K.
Chem. Commun. 1999, 1323.
References
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atmosphere, 3a (160 mg, 0.6 mmol) was added drop-
wise and then stirred for additional 30 min. After evap-
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3
MHz) l 6.87 (d, JFH=36.4 Hz, 1H), 7.4–7.8 (m, 8H),

6102
H. Hata et al. / Tetrahedron Letters 43 (2002) 6099–6102
7.90 (d, J=6.1 Hz, 2H); 19F NMR (CDCl3, 188 MHz,
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3
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1F). Anal. calcd for C15H11FO: C, 79.63; H, 4.90.
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(Z)-5g) were determined by NOE difference NMR