Defluorinative silylation toward a selective preparation of
a-trimethylsilyl-a,a-difluoroacetates from trifluoroacetates
Kenji Uneyama* and Go Mizutani
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan.
E-mail: uneyamak@cc.okayama-u.ac.jp
Received (in Cambridge, UK) 18th January 1999, Accepted 2nd March 1999
Table 1 Electrochemical preparation of 2, 3 and 4a
Electrochemical reduction of n-hexyl trifluoroacetate 1a in
MeCN, involving Bu4NBr, TMSCl, and Et3N using an H-
Yield(%)c
type divided cell equipped with carbon plate as an anode and
TMSCl/
lead plate as a cathode at 50 °C, provided n-hexyl a-
trimethylsilyl-a,a-difluoroacetate 2a in 62% yield, which is a
promising precursor of an alkoxycarbonyldifluoromethyl
carbanion equivalent and can be alkylated at the a-carbon
by fluoride ion catalysis.
Entry
R
equiv.b
T/°C
2
3
4
1
2
3
4
5
n-C6H13
But
Et
n-C6H13
Et
4
4
4
4
1
50
50
50
0
62 (68)
58 (68)
47 (65)
41
0
< 1
0
0
< 1
< 1
(18)
0
< 1
0
< 5
(21)d
Difluoromethylene compounds have become one of the most
important synthetic targets because of their unique biological
activity.1 Among the various difluorinated building blocks,
difluoroketene silyl acetals 3 have often been employed for
syntheses of difluorinated b-amino-b-hydroxy esters and b-
ethoxycarbonyldifluoromethyl-b-lactams under mild condi-
tions.2 However, they are unstable in the presence of moisture3
and zinc salts, so that they must be employed mostly in situ soon
after their generation by Reformatsky reaction of halodi-
fluoroacetates, and are utilized for alkylation in Lewis acid
catalyzed carbon–carbon bond formation at the difluoro-
methylene carbon. Here we describe a first selective preparation
of a-trimethylsilyl-a,a-difluoroacetates 2,4,5 a stable and
isolable alternative of 3, by electrochemical reductive de-
fluorination6 of trifluoroacetates, which are more readily
available than halodifluoroacetates, and its fluoride ion cata-
lyzed selective alkylation at the a-carbon [eqn. (1)].7
a Reagents and conditions: 1 (5 mmol), TMSCl (20 mmol), Et3N (20 mmol),
Bu4NBr (12 mmol), in MeCN (70 ml), 80 mA cm22, 2 F mol21
.
b Relative
to 1, Isolated yield (yield in parenthesis obtained by 19F NMR). 1 was
c
d
recovered in 33%.
2 was observed even in ethyl and tert-butyl esters [R = Et
(47%), and But (58%)].
Fluoride ion catalyzed generation of the alkoxycarbonyldi-
fluoromethyl carbanion and its alkylation were performed with
benzyl bromide (64%), benzoyl chloride (60%) and benzalde-
hyde (82%), respectively (Scheme 1). This alkylation under
basic conditions9 is an alternative to Lewis acid catalyzed
alkylation of ketene silyl acetals 3.2
i (for 5a)
ii (for 5b)
iii (for 5c)
O
O
TMS
E
OC6H13
O
OC6H13
O
Electroreduction
F
F
2a
F
F
TMS
(1)
OR
CF3
TMSCl, Bu4NBr, Et3N, MeCN
(C) - (Pb)
OR
5a E = Bn 64%
F
F
b E = Bz 60%
1
2
c E = PhCH(OH) 82%
Scheme 1 Reagents and conditions: i, PhCHO (3.0 mmol), TBAF (1.0
mmol), THF, 278 °C, 1 h; ii, BnBr (1.0 mmol), KF (1.2 mmol), CuI (1.5
mmol), DMF, 80 °C, 5 h; iii, BzCl (3.0 mmol), KF (2.0 mmol), CuI (1.5
mmol), DMF, 80 °C, 10 h.
O
O
OTMS
F
CF3
OR
OR
F
F
F
4
3
We are grateful to the Ministry of Education, Science, Sports
and Culture of Japan for financial support (No. 09305058) and
the SC-NMR Laboratory of Okayama University for 19F NMR
analysis.
Electrochemical reduction of n-hexyl trifluoroacetate was
conducted in MeCN involving Bu4NBr, Et3N and TMSCl using
an H-type divided cell (with a sintered glass filter) equipped
with carbon plate as an anode and lead plate as a cathode at
50 °C.† The product selectivity was found to be remarkably
dependent on both reaction temperature and the concentration
of TMSCl. At 50 °C the desired a-silylated acetate 2 was
formed selectively in the presence of an excess of TMSCl (4
equiv.). On the other hand, a mixture of 2 and ketene silyl acetal
3 was formed at 0 °C in the presence of an excess of TMSCl
(Table 1). Two-electron reduction followed by defluorination
leads to the formation of the b,b-difluoro enolate which is
trapped with TMSCl to give 3 as the kinetic product. C-
Silylated product 28,9 was the thermodynamic product since
ketene silyl acetal 3 was found to be transformed to 2 under the
electrolysis conditions at 50 °C. Meanwhile, formation of
Claisen condensation product 4 was accompanied by 2 in the
presence of only 1 equiv. of TMSCl. The selective formation of
Notes and references
† Typical procedure for 2a: the electroreductive defluorination of n-hexyl
trifluoroacetate 1a (5 mmol) was carried out using a Pb cathode (2 3 5 cm2)
and a carbon anode in anhydrous MeCN (70 ml) containing Bu4NBr (12
mmol), Et3N (20 mmol) and TMSCl (20 mmol) in an H-type divided cell.
A constant current of 80 mA was passed at 50 °C under an argon atmosphere
until 1a was consumed (2 F mol21). Selected data for 2a: colorless oil, bp
80 °C (2 mmHg) (bath temperature) (62%); nmax(neat)/cm21 1756 (CNO);
dH(CDCl3, 200 MHz) 0.23 (s, 9 H), 0.89 (t, 3 H, J 6.6), 1.30–1.41 (m, 6 H),
1.62–1.72 (m, 2 H), 4.23 (t, 2 H, J 6.8); dF(CDCl3, 188 MHz, C6F6 as an
internal standard) 38.7 (s, 2 F); dC(CDCl3, 50 MHz) 4.9, 13.9, 22.5, 25.4,
28.4, 31.3, 66.2, 121.0 (t, JCF 269, CF2), 166.3 (t, JCF 26, CNO); m/z (GC/
MS) 168 (M 2 C6H12), 152 (M 2 OC6H12), 73 (M 2 CF2CO2C6H13
)
(Found: C, 52.04; H, 8.99. Calc.: C, 52.35; H, 8.79%).
Chem. Commun., 1999, 613–614
613
Uneyama, Kenji
