Mg0-promoted selective C-F bond cleavage of trifluoromethyl ketones: A convenient method for the synthesis of 2,2-difluoro enol silanes

Article abstract of DOI:10.1039/a903681d

2,2-difluoro enol silyl ethers were readily prepared by Mg⁰ promoted selective defluorination of trifluoromethyl ketones in the presence of TMSCI, which involves C-F bond cleavage.

Full text of DOI:10.1039/a903681d

Mg0-promoted selective C–F bond cleavage of trifluoromethyl ketones: a
convenient method for the synthesis of 2,2-difluoro enol silanes
Hideki Amii, Takeshi Kobayashi, Yasushi Hatamoto and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama
700-8530, Japan. E-mail: uneyamak@cc.okayama-u.ac.jp
Received (in Cambridge, UK) 7th May 1999, Accepted 8th June 1999
Table 1 Mg0-promoted defluorinative silylation of trifluoromethyl ketones
2,2-Difluoro enol silyl ethers were readily prepared by Mg0
promoted selective defluorination of trifluoromethyl ketones
in the presence of TMSCl, which involves C–F bond
cleavage.
1a
Product Yieldb
Entry
1
R
T/°C
t/min
3
(%)
Difluoro enol silyl ethers are synthetic equivalents of enolates
of a,a-difluoro ketones and useful synthons for difluoro
compounds, which provide a wide repertoire of bioactive
fluorinated compounds.1 One of the well-established methods
for preparing difluoro enol silyl ethers is dehalogenation from
halodifluoromethyl groups.2 Selective defluorination of the
trifluoromethyl group is a promising method for preparing
difluoro compounds due to the broad and easy availability of
trifluoromethylated compounds. However, there are very few
successful cases of the selective demonofluorination from a
trifluoromethyl group.3–7 Recently, we have reported electro-
reductive methods for difluoro enol silyl ethers8 and difluoro
enamines9 using trifluoromethyl ketones and imines as starting
materials. A key feature of these methodologies is the
selectivity of defluorination which derives from the higher
reduction potentials of the product enols and enamines than
those of the parent keto systems.8 Here, we report the first
successful Mg0-promoted selective defluorination of trifluoro-
methyl ketones 1 in the presence of TMSCl by means of a
process involving C–F bond cleavage [eqn. (1)],10 which
provides a highly efficient access to a variety of 2,2-difluoro
enol silyl ethers.
1
2
3
4
5
6
7c
8c
a
1a
1b
1c
1d
1e
1f
Ph
0
0
0
0
0
0
0
0
20
20
20
20
25
25
30
30
3a
3b
3c
3d
3e
3f
91
89
87
98
97
97
56
62
4-MeOC6H4
4-CF3C6H4
4-ClC6H4
2-furyl
2-thienyl
C6H13
1g
1h
3g
3h
Cy
Unless otherwise stated, the reactions were performed on a 0.6 mmol
scale in THF. b NMR yield, which was calculated by 19F NMR integration
of product 3 relative to 1,3-bis(trifluoromethyl)benzene internal standard.
c DMF was used as solvent, and 8 equiv. of Mg was used.
aromatic and heteroaromatic ketones 1a–f generally gave good
yields, and the presence of electron-withdrawing and -donating
groups had little effect on the yields. Notably, CF3-arene and
Cl-arene functionalities were compatible with the present
reaction conditions; the reductive cleavage of the benzylic C–F
bond13 or aromatic C–Cl bond14 did not occur (entries 3 and
4).
The formation of 3 can be explained by assuming the
pathway pictured in Scheme 1. Initially, the intermediate ketyl
species 4 is generated in the reaction of Mg0 with a ketone 1,
which is further reduced to anion species 5 by Mg. The resultant
b-fluorinated organomagnesium species 5 readily undergoes b-
elimination to form 2. In general, the cleavage of a C–F bond is
not easy due to the large bond energy (ca. 552 kJ mol21).
However, the bond breaking does occur rather easily when the
CF3 group is attached to a p-system because electron ac-
ceptance into the carbonyl group and subsequent extrusion of
the fluoride ion may make large contributions to the driving
force of the reaction. The reduction potential of aromatic
ketones (1a–f) is more negative than that of aliphatic ones (1g
and 1h). Therefore, the difference in reactivity between
aromatic ketones and aliphatic ones may derive from the
tendency to form ketyl anion species 3.
O
O
Mg0
–
(1)
CF2
R
CF3
R
C–F bond Cleavage
1
2
The reaction procedure is very simple. The mixture of 1a (6.0
mmol), TMSCl and Mg11 (12 mmol) in 2.4 ml of anhydrous
THF was stirred at 0 °C for 20 min [eqn. (2)].† After filtration,
the difluoro enol silyl ether 3a was obtained in 91% NMR
yield.
OSiMe3
O
Mg / Me3SiCl
F
(2)
R
CF3
R
THF or DMF
F
In particular, utilization of 2,2-difluoro enol silanes 3 is made
in aldol reactions.7 After simple filtration of the metal waste, the
crude products 3 were used directly in the next reaction without
1
3
Compared to previously available methods, this methodology
has several advantages: (i) the starting trifluoromethylated
materials are readily available directly from trifluoroacetates;
(ii) Mg as a reducing agent is cheap and easy to handle; and (iii)
selective formation of 2,2-difluoro enol silyl ethers is achieved
in a short reaction time.
As shown in Table 1, the same procedure for the selective
formation of 3 works well for a diverse group of aromatic,
heteroaromatic and aliphatic ketones, and the over-reduction
products were not detected.
In the cases of aromatic and heteroaromatic ketones 1a–f, the
reactions were completed within 25 min at 0 °C in THF (entries
1–6), as compared with the case of aliphatic ketones (1g and 1h)
which required DMF as a solvent (entries 7 and 8).12 Also,
MgLn
MgLn
R
O
O
O
Mg
Mg
F2C
F
R
•
CF3
R
CF3
MgLn
1
4
5
OMgLn
OSiMe3
Me3SiCl
F
F
R
R
F
F
6
3
Scheme 1
Chem. Commun., 1999, 1323–1324
1323

1 J. P. Whitten, C. L. Barney, E. W. Huber, P. Bey and J. R. McCarthy,
Tetrahedron Lett., 1989, 30, 3649; Z.-M. Qiu and D. J. Burton, J. Org.
Chem., 1995, 60, 5570; K. Iseki, Y. Kuroki, D. Asada and Y. Kobayashi,
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2 M. Kuroboshi, and T. Ishihara, Bull. Chem. Soc. Jpn., 1990, 63, 426.
3 Base-catalysed dehydrofluorination of 2,2,2-trifluoroethyl groups: J. A.
Haward, W. H. Owton, J. M. Percy and M. K. Rock, Tetrahedon, 1995,
51, 10 289; J. Ichikawa, T. Sonoda and H. Kobayashi, Tetrahedon Lett.,
1989, 30, 1641.
4 Defluorination via Brook rearrangement for acylsilanes: F. Jin, Y. Xu
and W. Huang, J. Chem. Soc., Perkin Trans. 1, 1993, 795; T. Brigaud,
P. Doussot and C. Portella, J. Chem. Soc., Chem. Commun., 1994,
2117.
purification due to the instability of 3. When benzaldehyde was
added to a solution of 3a and TiCl4 at 278 °C, the aldol adduct
7a was formed [eqn. (3)] in 71% isolated yield (from 1a).
OH
O
O
(1) Mg / Me3SiCl
(2) PhCHO / TiCl4
(3)
Ph
R
CF3
R
F
F
1a R = Ph
7a
(71%)
(78%)
(38%)
(42%)
d R = 4-ClC6H4
g R = C6H13
h R = Cy
d
g
h
5 Reductive dechlorofluorination of a-chloro-a-alkoxy-b,b,b-trifluoro-
propionates: G.-Q. Shi and W.-L. Cai, J. Org. Chem., 1995, 60, 6289.
6 SN2A type reaction to trifluoromethyl groups: J.-P. Bégué, D. Bonnet-
Delpon and M. H. Rock, Synlett, 1995, 659.
7 Reactions of the silyllithium and silylmagnesium reagents with
trifluoromethyl ketones: I. Fleming, R. S. Roberts and S. C. Smith,
J. Chem. Soc., Perkin Trans. 1, 1998, 1215.
In conclusion, Mg0-promoted selective defluorination of a
series of trifluoromethyl ketones provides a promising route to
difluoro enol silanes.
We thank the SC-NMR laboratory of Okayama University
for 19F NMR analysis and the Ministry of Education, Science,
Sports and Culture of Japan for financial support (Grant-in-Aid
for Scientific Research, No. 09305058).
8 K. Uneyama, K Maeda, T. Kato and T. Katagiri, Tetrahedron Lett.,
1998, 39, 3741.
9 K. Uneyama and T. Kato, Tetrahedron Lett., 1998, 39, 587.
10 For a recent review on metal-mediated C–F bond activation, see: J.
Burdeniuc, B. Jedlicka and R. H. Crabtree, Chem. Ber./Recl., 1997, 130,
145.
11 A flask containing Mg turnings was flame-dried under under vacuum,
cooled, and then flushed with argon. Commercially available Mg
turnings (Nacalai tesque, Inc.) were used without further activation of
the magnesium surface, such as iodine, dibromoethane or ultrasound
treatment.
Notes and references
† Typical procedure for 3a: To TMSCl (2.6 g, 24 mmol) in freshly distilled
THF (24 ml) and Mg (290 mg, 12 mmol) cooled down to 0 °C under an
argon atmosphere, trifluoroacetophenone (1.04 g, 6.0 mmol) was added
dropwise and then stirred for an additional 20 min. After evaporation of
most of the THF, hexane (20 ml) was added to the residue, and the resulting
salt was filtered and the filtrate concentrated to give 1.21 g (ca. 0.53 mmol)
of crude product (the crude product 3a had purity > 95%).
12 Y. Ishino, Y. Kita, H. Maekawa, T. Ohno, Y. Yamasaki, T. Miyata and
I. Nishiguchi, Tetrahedron Lett., 1999, 40, 1349.
To a solution of crude 3a and benzaldehyde (1.27 g, 12 mmol) in CH2Cl2
(10 ml) cooled down to 278 °C, was added dropwise a solution of TiCl4 (6
mmol) in CH2Cl2 (10 ml). Then the reaction mixture was quenched with aq.
NH4Cl, and the organic layer was washed with brine and dried over
Mg2SO4. Purification of the products by chromatography on silica gel
(hexane–EtOAc 5+1) provided 7a (1.18 g, 71% from 1a) as a colorless oil.
Selected data for 7d: 3512 cm21 (nOH), 1696 cm21 (nCO); dH(CDCl3, 200
MHz) 3.05 (d, J 3.6, 1 H), 5.35 (ddd, JHF 18.6, 7.6, 3.6, 1 H), 7.2–7.5 (m,
7 H), 7.9–8.0 (m, 2 H); dF(CDCl3, 188 MHz, C6F6 as an internal standard)
45.2 (dd, JFF 290.7, JHF 18.6, 1 F), 56.9 (dd, JFF 290.7, JHF 7.6, 1 F).
13 Electroreductive defluorination of fluoromethylarenes: C. Saboureau,
M. Troupel, S. Sibille and J. Périchon, J. Chem. Soc., Chem. Commun.,
1989, 1138; C. P. Andrieux, C. Combellas, F. Kanoufi, J.-M. Savéant
and A. Thiébault, J. Am. Chem. Soc., 1997, 119, 9527.
14 For a recent review, see: V. V. Grushin and H. Alper, Chem. Rev., 1994,
94, 1047.
Communication 9/03681D
1324
Chem. Commun., 1999, 1323–1324