Preparation and synthetic application of a novel ketene silyl acetal of methyl trifluoropyruvate

Article abstract of DOI:10.1021/jo051242q

A novel trifluoromethyl ketene silyl acetal (4) of methyl trifluoropyruvate (1) was prepared in 82% yield by metal Mg reduction in a (TMS)Cl/THF system. Subsequent carbon-carbon bond formation such as Mukaiyama aldol, Michael addition, and other nucleophi

Full text of DOI:10.1021/jo051242q

Preparation and Synthetic Application of a Novel Ketene Silyl
Acetal of Methyl Trifluoropyruvate
Go Takikawa, Toshimasa Katagiri, and Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, 3-1-1 Tsushima-naka,
Okayama 700-8530, Japan
uneyamak@cc.okayama-u.ac.jp
Received June 16, 2005
A novel trifluoromethyl ketene silyl acetal (4) of methyl trifluoropyruvate (1) was prepared in 82%
yield by metal Mg reduction in a (TMS)Cl/THF system. Subsequent carbon-carbon bond formation
such as Mukaiyama aldol, Michael addition, and other nucleophilic reactions of 4 at the
trifluoromethylated carbon with various electrophiles gave various coupling products in high yields.
SCHEME 1. Nucleophilic Addition of
Trifluoropyruvates
Introduction
Trifluoropyruvates and their derivatives have been
widely used in the fields of medicinal, agricultural, and
advanced materials.1 Their molecular transformations
have been extensively investigated. In particular, carbon-
carbon bond formation at the R-carbon to the CF3 group
is an efficient route to quaternary trifluoromethylated
compounds. Nonetheless, such carbon-carbon bond for-
mations have been mostly attained by reactions with
nucleophiles: alkylation with Grignard reagents2 or
acetylene anion,3 ene reaction with alkenes,4 aldol reac-
tion with enolates,5 and Friedel-Crafts reactions.6 On
the other hand, only two reactions of 1 with electrophiles
have been reported: Zn(Cu)-promoted cross-coupling of
1 with protected glyceraldehyde to give diol 27 and
reductive pinacol coupling of 1, leading to diols 3 (Scheme
1).8-10
It is quite relevant from the viewpoint of synthetic
organofluorine chemistry to exploit the strategic varia-
tions for the utilization of 1 as a nucleophile. To attain
such a purpose, dipole inversion of either substrates or
reagents with infusion of electrons would be necessary
for carbon-carbon bond formation of 1 with electrophiles.
Fortunately, the pyruvate 1 has a low-lying LUMO, due
(1) (a) Prakash, G. K. S.; Yan, P.; Torok, B.; Olah, G. A. Synlett 2003,
527-531. (b) Kato, K.; Fujii, S.; Gong, Y. F.; Tanaka, S.; Katayama,
M.; Kimoto, H. J. Fluorine Chem. 1999, 99, 5-7. (c) Bravo, P.;
Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998, 39,
7771-7774.
(2) (a) Blay, G.; Fernandez, I.; Marco-Aleixandre, A.; Monje, B.;
Pedro, J. R.; Ruiz, R. Tetrahedron 2002, 58, 8565-8571. (b) Wucherpfen-
nig, U.; Logothetis, T. A.; Eilitz, U.; Burger, K. Tetrahedron 1996, 52,
143-148. (c) Soloshonok, V. A.; Gerus, I. I.; Yagupol’skii, Yu L.;
Kukhar, V. P. Zh. Org. Khim. 1987, 23, 1441-1447.
(3) Golubev, A. S.; Sergeeva, N. N.; Hennig, L.; Kolomiets, A. F.;
Burger, K. Tetrahedron 2003, 59, 1389-1394.
(4) (a) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahe-
dron Lett. 2004, 45, 183-185. (b) Soloshonok, V. A.; Rozhenko, A. B.;
Butovich, I. A.; Kukhar, V. P. Zh. Org. Khim. 1990, 26, 2051-2056.
(5) (a) Shi, G.; Xu, Y. J. Org. Chem. 1990, 55, 3383-3386. (b)
Golubev, A. S.; Galakhov, M. V.; Kolomiets, A. F.; Fokin, A. V. Izv.
Akad. Nauk SSSR, Ser. Khim. 1989, 2127-2130. (c) Saloutin, V. I.;
Piterskikh, I. A.; Pashkevich, K. I. Zh. Org. Khim. 1988, 24, 701-704.
(6) (a) Gathergood, N.; Zhuang, W.; Jorgensen, K. A. J. Am. Chem.
Soc. 2000, 122, 12517-12522. (b) Ding, R.; Zhang, H. B.; Chen, Y. J.;
Liu, L.; Wang, D.; Li, C. J. Synlett 2004, 555-557.
(7) Eilitz, U.; Bottcher, C.; Sieler, J.; Gockel, S.; Haas, A.; Burger,
K. Tetrahedron 2001, 57, 3921-3925.
(8) Soloshonok, V. A.; Gerus, I. I.; Yagupol’skii, Yu L.; Kukhar, V.
P. Zh. Org. Khim. 1987, 23, 1441-1447.
(9) Markova, E. A.; Kolomiets, A. F.; Fokin, A. V. Izv. Akad. Nauk
SSSR, Ser. Khim. 1992, 1408-1411.
(10) Krespan, C. G. J. Fluorine Chem. 1994, 66, 311-316.
10.1021/jo051242q CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/24/2005
J. Org. Chem. 2005, 70, 8811-8816
8811

Takikawa et al.
SCHEME 2. Strategy for Preparation of Ketene
Silyl Acetal
SCHEME 3. Mg-Promoted Transformation of
MTFP (1)
a Isolated yield. The yield in parentheses was analyzed by 19F
NMR integration of product 4 relative to hexafluorobenzene as
an internal standard.
to the electron-withdrawing effect of the CF3 group, and
easily accepts electrons. Moreover, we have developed a
facile method to infuse electrons to carbonyl moieties by
the use of a Mg-(TMS)Cl (chlorotrimethylsilane) sys-
tem.11 On this basis, we are interested in the idea that
the ketene silyl acetal 4 is a reduced pyruvate, a potential
anion equivalent of 1, which can react with electrophiles
at the keto carbonyl carbon.
SCHEME 4. Formation of Byproducts 8 and 9
from 4
Ketene silyl acetals are, in general, prepared by base-
catalyzed enolization of esters followed by trapping of the
enolates with (TMS)Cl.12 However, R-keto esters have
never been used for this purpose. Our key idea relies on
a practical synthesis of ketene silyl acetal 4 from 1 by
Mg metal reduction and utilization of 4 as a trifluoro-
methyl synthetic block.
The magnesium-(TMS)Cl system has been used for
C-F bond activation of the trifluoromethyl group at-
tached to π-electron systems such as carbonyl, iminyl,
and phenyl groups. Trifluoromethyl ketones,13 imines,14
esters,15 and aromatic compounds16 can be transformed
to difluoro enol silyl ethers, difluoro enamines, R-silyl
acetates, and difluorobenzylsilanes, respectively. We were
interested in seeing whether the Mg-promoted C-F bond
activation of trifluoromethyl ketones could be applicable
for nondefluorinative functionalization of 5. Namely,
attachment of the carboalkoxy group on the trifluoro-
acetyl moiety as an anion-stabilizing group would retard
defluorination and thus promote the formation of ketene
silyl acetal, although trifluoroacetyl derivatives 5 bearing
alkyl, aryl, phenoxy, and vinyl groups undergo defluori-
nation exclusively, leading to 7 via 6, on treating them
with metal Mg (Scheme 2).
methylated ketones, a defluorination product was not
obtained. Instead, pinacol 3 was produced selectively as
a diastereomeric mixture at room temperature in 92%
isolated yield with a diastereomeric ratio of 56:44. The
reaction at -30 °C gave ketene silyl acetals 4 selectively
in 82% yield as a mixture of stereoisomers.
The 19F NMR analyses of the crude reaction mixture
suggested a quantitative production of 4 at a reaction
temperature of -30 °C. However, ketene silyl acetal 4
was found to be both moisture- and oxygen-sensitive
under acidic conditions so that about 20% of the product
4 was lost during the workup procedure. For the effective
isolation of 4, exposure of the products to water, oxygen,
and Lewis acid must be carefully avoided. In particular,
MgCl2 generated in the reaction should be completely
removed from ketene silyl acetal 4; otherwise, the yield
of 4 is drastically lowered. The addition of 1,4-dioxane
for complexation with magnesium salt to form an in-
soluble MgCl2-dioxane complex polymer, followed by
Celite filtration under an argon atmosphere, was found
to be effective in removing the MgCl2 salt.17 Complete
removal of MgCl2 made the purification of 4 very easy.
The condensed crude ketene silyl acetals 4 were finally
purified by distillation. The pure ketene silyl acetals 4
are stable even on distillation at 120 °C and on being
kept in a mixture of benzene and water at room temper-
ature for 1 h. Unless MgCl2 was completely removed, a
large amount of 4 was transformed to a mixture of
byproducts 8 and 9, and the isolated yield of 4 was poor
(Scheme 4).
We describe here a new preparation of a novel CF3-
substituted ketene silyl acetal (4) by reductive transfor-
mation of 5 (R ) CO2Me) in a Mg-(TMS)Cl/THF system,
and nucleophilic additions of 4 with various electrophiles.
Results and Discussion
Mg(0)-Promoted Preparation of Ketene Silyl Ac-
etal 4 from Methyl Trifluoropyruvate (MTFP, 1). 1
was at first subjected to Mg-promoted reduction (Scheme
3). Contrary to the conventional reactions of trifluoro-
Optimization of the Mukaiyama Aldol Reaction
of 4. The chemically pure 4 was successfully prepared,
which was usable for further reactions. First, the effect
of Lewis acid in the Mukaiyama aldol reaction of 4 was
optimized, and the results are summarized in Table 1.
Mukaiyama aldol reaction of 4 with aldehydes was
successfully conducted under conventional (TMS)OTf-
promoted conditions, and the desired aldol compounds
were obtained in high yields. The silyl acetal 4 was
(11) Uneyama, K.; Amii, H. J. Fluorine Chem. 2002, 114, 127-131.
(12) Yokozawa, T.; Nakai, T.; Ishikawa, N. Tetrahedron Lett. 1984,
25, 3991-3994.
(13) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323-1324.
(14) Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41,
7893-7896.
(15) Amii, H.; Kobayashi, T.; Uneyama, K. Synthesis 2000, 2001-
2003.
(16) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J. Org. Chem.
2001, 66, 7216-7218.
(17) Sobota, P.; Duda, B. J. Organomet. Chem. 1987, 332, 239-245.
8812 J. Org. Chem., Vol. 70, No. 22, 2005

Ketene Silyl Acetal of Methyl Trifluoropyruvate
TABLE 1. Effects of a Lewis Acid on the Mukaiyama
Aldol Reaction of 4a
SCHEME 5. Results of the Mukaiyama-Michael
Reaction
results (yield, %)b
Lewis
entry
acid (equiv)
10cc
11cc
12cc
ND
ND
8
9
1
2
3
4
5
6
(TMS)OTf (0.05) 94
5
1
ND
3
1
4
ZnBr2 (1.2)
ZnI2 (1.3)
AlCl3 (1.2)
SnCl4 (1.2)
TiCl4 (1.1)
60
54
26
2
31
33
1
trace ND
45
23
ND
decomp
in the Mukaiyama aldol reaction of ketene silyl acetals
4 was examined. The results are summarized in Table
2.
trace 38
20 39
a ND means not detected. b After workup, the yields were
analyzed by 19F NMR and were calculated by 19F NMR integration
of the product relative to hexafluorobenzene as an internal
standard. c 10c, R1 ) R2 ) SiMe3; 11c, R1 ) H, R2 ) SiMe3; 12c,
R1 ) R2 ) H.
The desired cross-aldol compounds were obtained as
diastereomeric mixtures in high yields. Disilylated aldol
products of 10a and 10b were stable under neutral
conditions and easily isolable by column chromatography
with neutralized silica gel. However, disilylated com-
pounds 10c-e were hydrolyzed in part and 10f-h were
mostly hydrolyzed, when isolated. They seemed to be
converted into monosilylated compounds during the silica
gel chromatographic isolation process. The monosilylated
compounds were also unstable and decomposed gradually
via retro-aldol reaction. 10a-h were converted to the
stable desilylated diols 12a-h under hydrolysis condi-
tions in a homogeneous MeOH-THF-HCl(aq) system.
The desilylation in a heterogeneous system such as CH2-
Cl2-HCl(aq) proceeded very slowly, thus promoting retro-
aldol reaction, which resulted in a low yield of the desired
diols. Aldol products 10g and 10h from aliphatic alde-
hydes were not isolated due to easy desilylation and
retro-aldol reaction. The NMR, GC-MS, and GC analyses
of the reaction mixture obviously indicated that aldol
compounds were once formed.
Mukaiyama-Michael Reaction with r,â-Unsatur-
ated Carbonyl Compounds. Next, 1,4-additions of
ketene silyl acetals 4 to R,â-unsaturated carbonyl com-
pounds were studied. The results are shown in Scheme
5.
A lower reaction temperature was found essential to
avoid unfavorable double Mukaiyama-Michael reaction
and to improve the yields of the target compounds 13 and
14. Thus, a longer reaction time was needed. However,
converted to 10c under Mukaiyama aldol reaction condi-
tions with ZnBr2, ZnI2, and AlCl3, but the products were,
somewhat, complicated. The starting substrate was easily
hydrolyzed to give a silylated lactate (8) via desilylative
protonation when ZnBr2 and ZnI2 were used. The hy-
drolysis of 4 would be promoted by water, which probably
comes from the moisture-contaminated zinc halides.
Complete removal of such water from ZnBr2 and ZnI2 by
the conventional drying method is difficult. In the reac-
tion with AlCl3, desilylation occurred without regioselec-
tivity on workup of the reaction mixture. Monosilylated
aldol compound 11c easily underwent retro-aldol reaction
when 11c was submitted to silica gel chromatography
for isolation. The reaction of 4 with SnCl4 gave a partial
formation of protonated 8 and a considerable amount of
defluorinated compound 9. The reaction with TiCl4 was
so strong that the reaction resulted in complete decom-
position of ketene silyl acetal 4, and no desired compound
was obtained. On the basis of these results, (TMS)OTf
was found to be the best of the Lewis acids so far
examined for the Mukaiyama aldol reaction with various
electrophiles.
Scope of the Mukaiyama Aldol Reaction with
Aldehydes. Next, the scope of the aldehyde electrophiles
TABLE 2. Results of the Mukaiyama Aldol Reaction of 4 with Aldehydes
entry
R1
product 10, yielda (%)
[THF] (M)
product 12, yieldb (%)
1
2
3
4
5
6
7
8
4-CH3OC6H4
3-ClC6H4
Ph
4-CF3C6H4
furyl
4-CH3C6H4
Ph(CH2)2
CH3CHdCH
10a, 97 (98)
10b, 86 (98)
10c, 60 (94)
10d, 58 (87)
10e, 50 (87)
10f, 20 (88)
10g (57)c
0.2
0.3
0.4
0.5
0.5
0.5
0.2
0.5
12a, 87
12b, 79
12c, 79
12d, 68
12e, 73
12f, 88
12g, 53
12h, 64
10h (76)c
a Isolated yield. Yields in parentheses are GC yields, which were calculated by the percentage of GC integration of products 10. b Isolated
yield. Yields of compounds 12 were overall yields from 4 without isolation of 10. c The disilyl compounds 10g and 10h were too unstable
to be purified, so they were converted to diols 12g and 12h without a purification process.
J. Org. Chem, Vol. 70, No. 22, 2005 8813

Takikawa et al.
TABLE 3. Reaction with Various Electrophiles
a Isolated yield. b PMP means 4-CH3OC6H4.
in the reaction of other Michael acceptors such as
acrylonitrile, methyl acrylate, and crotonaldehyde, Michael
addition products were not obtained. The rate of poly-
merization of these Michael acceptors seemed to be faster
than that of the reaction with 4 under a wide range of
temperature conditions.
simple preparation of silyl acetal 4 and the scope of its
applications for C-C bond formation with various elec-
trophiles suggested the high potential of 4 as a triflu-
oromethyl-substituted building block which behaves as
a synthetic equivalent of a carbanion species at the keto
carbonyl group of trifluoropyruvate.
Nucleophilic Reactions of 4 with Other Electro-
philes. Nucleophilic reactions of 4 with other electro-
philes were examined. The results are summarized in
Table 3.
Experimental Section
Preparation of a Pinacol (2,3-Dihydroxy-2,3-bistri-
fluoromethylsuccinic Acid Dimethyl Ester, 3). A suspen-
sion of (TMS)Cl (0.5 mL, 4.0 mmol) in freshly distilled THF (9
mL) and Mg (73 mg, 3.0 mmol) was kept at 20-30 °C under
an argon atmosphere, MTFP (1; 156 mg, 1.0 mmol) in dry THF
(1 mL) was added dropwise with a cannula (1 h) at 20-30 °C
under an argon atmosphere. The reaction mixture was stirred
for an additional 7 h at 20-30 °C. After removal of excess
(TMS)Cl and THF in vacuo (ca. ∼30 mmHg), the reaction
mixture was poured into 20 mL of 10% HCl(aq) at 0 °C. Then,
the resulting mixture was extracted with Et2O (10 mL × 3),
and the organic layer was washed with brine. After removal
of the Et2O in vacuo (ca. ∼50 mmHg), 3 mL of THF and 0.5
mL of 10% HCl(aq) were added to the resulting oil. To the
solution was added TBAF in THF (1.5 mL, 1.5 mmol) dropwise
with a cannula (10 min) at 10-20 °C, and the reaction mixture
was stirred for an additional 1 h at 20-30 °C. After evapora-
tion of most of the THF, 5 mL of 10% HCl(aq) was added to
the residue, the reaction mixture was extracted with Et2O (10
mL × 6), and the organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, purification
of the crude product by chromatography on silica gel (n-hexane:
Et2O ) 8:1) afforded 3 (144 mg, 92%) as a white solid:
diastereomeric mixture (56:44 by 19F NMR); mp 102-104 °C;
Acylation with acyl halides proceeded quite smoothly
by TBAF in the presence of molecular sieves 3A (MS-
3A), and R,R-disubstituted â-keto esters 15a and 15b
were readily obtained in high yields (entries 1 and 2). In
the absence of MS-3A, the reaction gave â-keto esters in
low yield with byproduction of a large amount of hydro-
lyzed compound 8. Mukaiyama-type aldol reaction with
benzaldehyde dimethyl acetal gave coupling compound
16a in 90% yield. However, Mannich-type coupling with
an aldimine as an electrophile proceeded very slowly
under the usual conditions using (TMS)OTf as Lewis
acid. Here, tris(pentafluorophenyl)borane was found to
be effective for this reaction of 4 with the electrophiles;
the desired compound 16b was obtained in 15% yield.
(TMS)OTf did not promote the Mukaiyama aldol reaction
of 4 with acetophenone, but the use of B(C6F5)3 enabled
preparation of 16c in 14% yield.
Conclusion
IR (KBr) 3510, 3000, 1750, 1455 cm-1; H NMR (300 MHz) δ
1
Reduction of methyl trifluoropyruvate (1) with Mg
metal provided novel ketene silyl acetal 4 at -30 °C in
82% yield, while giving pinacol compound 3 at room
temperature selectively, but no difluoro enol silyl ether
9 was obtained. Ketene silyl acetals 4 could be used for
C-C bond formation by nucleophilic addition to electro-
philes such as aldehydes, acyl halides, and aldimines. The
3.98 (s, 6H, major), 4.00 (s, 6H, minor), 4.52 (s, 2H, minor),
4.53 (s, 2H, major); 19F NMR (282 MHz) δ 88.6 (s, 3F, minor),
88.9 (s, 3F, major); EI MS m/z (relative intensity) 255 (M+
-
59, 9), 158 (70), 69 (61), 59 (100). Anal. Calcd for C8H8F6O6:
C, 30.59; H, 2.57. Found: C, 30.44; H, 2.67.
Preparation of Ketene Silyl Acetals (1-Methoxy-1-
trimethylsilyloxy-2-trifluoromethyl-2-trimethylsilyloxy-
8814 J. Org. Chem., Vol. 70, No. 22, 2005

Ketene Silyl Acetal of Methyl Trifluoropyruvate
ethene, 4). Under an argon atmosphere, a mixture of Mg
(turnings) (2.8 g, 115.3 mmol) and (TMS)Cl (20.9 g, 192.2
mmol) was treated by ultrasound irradiation prior to the
reaction. To the mixture of Mg and (TMS)Cl in dry THF (180
mL) was added 1 (10.0 g, 64.1 mmol) in dry THF (20 mL)
dropwise with a cannula (1 h) at -30 °C under an argon
atmosphere, and the reaction mixture was stirred for an
additional 4 h at -30 °C. To the reaction mixture was added
1,4-dioxane (40 mL) at -30 °C, and then the reaction mixture
was stirred for an additional 1 h at room temperature.
Residual magnesium and dioxane-MgCl2 salt were separated
by filtration under an argon atmosphere through completely
dried Celite with an argon atmosphere pressure, and the
filtrate was washed with freshly dried n-heptane (200 mL).
THF, n-heptane, (TMS)Cl, and a half amount of 1,4-dioxane
were removed under reduced pressure (15 mmHg) at 0 °C, and
a solution of n-heptane (50 mL) was added. The resulting salt
was removed by filtration under an argon atmosphere through
completely dried Celite. Evaporation of the filtrate and distil-
lation (1 mmHg, 45-55 °C) provided a colorless oil of 4 (15.9
g, 82%) as a mixture of E/Z isomers (62:38 by 19F NMR): IR
(neat) 2968, 2900, 2850, 1698, 1450 cm-1; 1H NMR (300 MHz)
(E isomer) δ 0.19 (s, 9H), 0.25 (s, 3H), 3.64 (s, 3H), (Z isomer)
δ 0.19 (s, 9H), 0.27 (s, 9H), 3.60 (s, 3H); 19F NMR (282 MHz,
washed with brine and dried over Na2SO4. Purification of the
product by silica gel column chromatography (n-hexane:Et2O
) 3:1) afforded 12.
Data for 3,3,3-trifluoro-2-hydroxy-2-(1′-phenylhy-
droxymethyl)propanoic acid methyl ester (12c): 79%
yield; white powder; diastereomeric mixture (66:34 by 1H
NMR); mp 88-90 °C; IR (neat) 3515, 3055, 2990, 1755, 1505,
1
1463, 1456 cm-1; H NMR (300 MHz) δ 2.53 (d, J ) 9.0 Hz,
1H, minor), 2.84 (d, J ) 8.4 Hz, 1H, major), 3.71 (s, 3H, major),
3.92 (s, 1H, major), 4.00 (s, 3H, minor), 4.14 (s, 1H, minor),
5.21 (d, J ) 7.2 Hz, 1H, minor), 5.26 (d, J ) 8.1 Hz, 1H, major),
7.32-7.49 (m, 5H × 2, major and minor mixed); 19F NMR (282
MHz) δ 83.9 (s, 3F × 2, major and minor mixed); EI MS m/z
(relative intensity) 247 (M+ - 17, trace), 187 (8), 107 (100), 79
(91), 77 (48). Anal. Calcd for C11H11F3O4: C, 50.01; H, 4.20.
Found: C, 50.30; H, 4.45.
(TMS)OTf-Catalyzed Mukaiyama-Michael Reaction
of Ketene Silyl Acetal 4 with an r,â-Unsaturated Alde-
hyde (5-Oxo-2-trifluoromethyl-2-trimethylsilyloxypen-
tanoic Acid Methyl Ester, 13). To a mixture of 4 (302 mg,
1.0 mmol) and acrolein (56 mg, 1.0 mmol) in dichloromethane
(1 mL) which was cooled to -78 °C under an argon atmosphere
was added (TMS)OTf (22 mg, 10 mol %), and then the resulting
mixture was stirred for an additional 40 h. After being stirred
at -50 °C for 12 h, the resulting mixture was poured into 2%
NaHCO3(aq), and the organic products were extracted with
Et2O (20 mL × 2). The organic layer was washed with brine
and dried over Na2SO4. The residue was purified by silica gel
column chromatography (n-hexane:Et2O ) 10:1) to afford 13
in 93% yield as a colorless oil: diastereomeric mixture (the
diastereomeric ratio could not analyzed by 1H NMR, 19F NMR,
and GC); IR (neat) 2968, 2905, 2850, 2740, 1762, 1730, 1444
cm-1; 1H NMR (300 MHz) δ 0.17 (s, 9H × 2, major and minor
mixed), 2.17-2.35 (m, 2H × 2, major and minor mixed), 2.42-
2.64 (m, 2H × 2, major and minor mixed), 3.82 (s, 3H × 2,
major and minor mixed), 9.74 (t, J ) 0.9 Hz, 1H × 2, major
and minor mixed); 19F NMR (282 MHz) δ 84.9 (s, 3F × 2, major
CDCl3) (E isomer) δ 97.1 (s, 3F), (Z isomer) δ 97.8 (s, 3F); 13
C
NMR (151 MHz, C6D6) (E isomer) δ -0.6, -0.2, 56.0, 112.4 (q,
J ) 35.1 Hz), 123.7 (q, J ) 270.1 Hz), 150.5, (Z isomer) δ -0.3,
-0.1, 57.6, 113.6 (q, J ) 35.7 Hz), 123.9 (q, J ) 270.1 Hz),
151.0; EI MS m/z (relative intensity) 302 (M+, 5), 195 (60), 73
(100). Anal. Calcd for C10H21F3O3Si2: C, 39.71; H, 7.00.
Found: C, 39.76; H, 7.00.
Typical Procedure for (TMS)OTf-Catalyzed Mukaiya-
ma Aldol Reactions of Ketene Silyl Acetals 4 with
Aldehydes. To a mixture of 4 (302 mg, 1.0 mmol) and
aldehyde (1.0 mmol) in dichloromethane (1 mL) which was
cooled to -30 °C under an argon atmosphere was added
(TMS)OTf (11 mg, 5 mol %), and then the resulting mixture
was stirred for an additional 8 h. Then, the reaction mixture
was poured into 2% NaHCO3(aq), and the organic products
were extracted with diethyl ether (Et2O; 20 mL × 2). The
organic layer was washed with brine and dried over Na2SO4.
Purification of the product by silica gel column chromatogra-
phy (n-hexane:Et2O ) 20:1) afforded 10.
and minor mixed); EI MS m/z (relative intensity) 271 (M+
-
15, trace), 211 (82), 89 (100), 77 (92), 73 (93), 59 (52). Anal.
Calcd for C10H17F3O4Si: C, 41.95; H, 5.98. Found: C, 41.82;
H, 5.76.
(TMS)OTf-Catalyzed Mukaiyama-Michael Reaction
of Ketene Silyl Acetal 4 with an r,â-Unsaturated Ketone
(3,3,3-Trifluoro-2-(3-oxocyclohexyl)-2-trimethylsilyloxy-
propanoic Acid Methyl Ester, 14). To a mixture of 4 (302
mg, 1.0 mmol) and 2-cyclohexen-1-one (96 mg, 1.0 mmol) in
dichloromethane (1 mL) which was cooled to -78 °C under an
argon atmosphere was added (TMS)OTf (22 mg, 10 mol %),
and then the resulting mixture was stirred for an additional
24 h. After being stirred at -40 °C for 24 h, the resulting
mixture was poured into 2% NaHCO3(aq), and the organic
products were extracted with Et2O (20 mL × 2). The organic
layer was washed with brine and dried over Na2SO4. The
residue was purified by silica gel column chromatography (n-
hexane:Et2O ) 10:1) to afford 14 in 96% yield as a colorless
oil: diastereomeric mixture (75:25 by 19F NMR); IR (neat)
2964, 2900, 2875, 1766, 1724, 1454, 1440 cm-1; 1H NMR (300
MHz) δ 0.18 (s, 9H, minor), 0.19 (s, 9H, major), 1.38-1.69 (m,
3H × 2, major and minor mixed), 1.90-2.57 (m, 6H × 2, major
and minor mixed), 3.79 (d, J ) 0.3 Hz, 3H, minor), 3.82 (d, J
) 0.9 Hz, 3H, major); 19F NMR (282 MHz) δ 89.8 (s, 3F, major),
Data for 3,3,3-trifluoro-2-[phenyl(trimethylsilyloxy)-
methyl]-2-trimethylsilyloxypropanoic acid methyl ester
(10c): 60% yield; colorless oil; diastereomeric mixture (68:32
by 19F NMR); IR (neat) 3040, 2968, 2908, 1772, 1763, 1498,
1
1456 cm-1; H NMR (300 MHz) δ -0.05 (s, 9H, minor), 0.01
(s, 9H, major), 0.05 (s, 9H, major), 0.21 (s, 9H, minor), 3.73 (s,
3H, major), 3.87 (s, 3H, minor), 5.24 (s, 1H, minor), 5.28 (s,
1H, major), 7.27-7.39 (m, 5H × 2, major and minor mixed);
19F NMR (282 MHz, CDCl3) δ 87.6 (s, 3F, minor), 89.8 (s, 3F,
major); EI MS m/z (relative intensity) 393 (M+ - 15, trace),
302 (trace), 179 (100), 73 (55). Anal. Calcd for C17H27F3O4Si2:
C, 49.98; H, 6.66. Found: C, 50.07; H, 6.87.
Data for 3,3,3-trifluoro-2-(1′-phenylhydroxymethyl)-2-
trimethylsilyloxypropanoic acid methyl ester (11c): 5%
yield; white powder; mp 69-70 °C; IR (neat) 3598, 3000, 2945,
1
1770, 1510, 1470, 1455 cm-1; H NMR (300 MHz) δ 0.17 (s,
9H), 2.62 (d, J ) 8.4 Hz, 1H), 3.90 (s, 3H), 5.15 (d, J ) 8.1 Hz,
1H), 7.32-7.40 (m, 5H); 19F NMR (282 MHz) δ 89.2 (s, 3F); EI
MS m/z (relative intensity) 336 (M+, trace), 320 (10), 230 (75),
214 (100), 195 (58), 138 (34), 107 (77), 77 (60), 73 (38). Anal.
Calcd for C14H19F3O4Si: C, 49.99; H, 5.69. Found: C, 50.14;
H, 5.49.
90.1 (s, 3F, minor); EI MS m/z (relative intensity) 311 (M+
15, 92), 283 (52), 89 (100), 77 (74), 73 (93), 69 (68). Anal. Calcd
for C13H21F3O4Si: C, 47.84; H, 6.49. Found: C, 47.62; H, 6.48.
-
Typical Procedure for TBAF-Promoted Preparation
of Trifluoromethylated â-Keto Esters. To a mixture of 4
(302 mg, 1.0 mmol), dried MS-3A (400 mg), and acyl chloride
(1.0 mmol) in dichloromethane (1 mL) which was cooled to -20
°C under an argon atmosphere was added TBAF/THF (1 mol/L
solution, 1.2 mL, 1.2 mmol), and then the resulting mixture
was stirred for an additional 10 min. After removal of MS-3A,
the filtrate was poured into 5% HCl(aq), and the organic
Typical Procedure for Desilylation of Mukaiyama
Aldol Compounds. To a mixture of 10 (without purification,
1.0 mmol) in MeOH (5 mL) and THF (2-5 mL) was added
12% HCl(aq) (2.1 mL, 7 mmol), and then the resulting mixture
was stirred for an additional 6 h at 30 °C. After evaporation
of most of the MeOH and THF, the resulting residue was
extracted with Et2O (10 mL × 6). The organic layer was
J. Org. Chem, Vol. 70, No. 22, 2005 8815

Takikawa et al.
products were extracted with Et2O (20 mL × 2). The organic
layer was washed with brine and dried over MgSO4. Pure 15a
and 15b were obtained as a clear and colorless oil from silica
gel column chromatography (n-hexane:Et2O ) 10:1) as a
diastereomeric mixture.
Data for 2-benzoyl-3,3,3-trifluoro-2-hydroxypropanoic
acid methyl ester (15a): 86% yield; diastereomeric mixture
(50:50 by 19F NMR); colorless oil; IR (neat) 3090, 2968, 1775,
1748, 1700, 1610, 1592, 1460, 1445 cm-1; 1H NMR (600 MHz)
δ 3.89 (s, 3H), 5.71 (q, J ) 7.2 Hz, 1H), 7.50 (m, 2H), 7.65 (m,
1H), 8.12 (m, 2H); 19F NMR (282 MHz) δ 88.2 (s, 3F), 88.3 (s,
3F); EI MS m/z (relative intensity) 262 (M+, 12), 105 (100), 77
(44), 51 (20). Anal. Calcd for C11H9F3O4: C, 50.39; H, 3.46.
Found: C, 50.30; H, 3.65.
(TMS)OTf-Catalyzed Mukaiyama-Type Aldol Reaction
of Ketene Silyl Acetal 4 with Benzaldehyde Dimethyl
Acetal (3,3,3-Trifluoro-2-[(1′-phenyl)methoxymethyl]-2-
trimethylsilyloxypropanoic Acid Methyl Ester, 16a). To
a mixture of 4 (302 mg, 1.0 mmol) and benzaldehyde dimethyl
acetal (156 mg, 1.0 mmol) in dichloromethane (1 mL) which
was cooled to -20 °C under an argon atmosphere was added
(TMS)OTf (22 mg, 10 mol %), and then the resulting mixture
was stirred for an additional 2 h. The resulting mixture was
poured into 2% NaHCO3(aq), and the organic products were
extracted with Et2O (20 mL × 2). The organic layer was
washed with brine and dried over Na2SO4. The residue was
purified by silica gel column chromatography (n-hexane:Et2O
) 15:1) to afford 16a in 90% yield as a colorless oil: diaster-
eomeric mixture (74:26 by 19F NMR); IR (neat) 3100, 3060,
2990, 2940, 2855, 1780, 1765, 1508, 1468, 1450 cm-1; 1H NMR
(300 MHz) δ 0.01 (s, 9H, major), 0.16 (s, 9H, minor), 3.16 (s,
3H, minor), 3.26 (s, 3H, major), 3.76 (s, 3H, major), 3.89 (s,
3H, minor), 4.71 (s, 1H, minor), 4.78 (s, 1H, major), 7.26-7.35
(m, 5H × 2, major and minor mixed); 19F NMR (282 MHz) δ
88.4 (s, 3F, minor), 90.2 (s, 3F, major); EI MS m/z (relative
intensity) 335 (M+ - 15, trace), 187 (5), 121 (100), 77 (19). Anal.
Calcd for C15H21F3O4Si: C, 51.41; H, 6.04. Found: C, 51.47;
H, 5.96.
B(C6F5)3-Catalyzed Mannich-Type Reaction of Ketene
Silyl Acetal 4 with an Aldimine (3,3,3-Trifluoro-2-[(1′-
methanesulfonylamino)(4-methoxyphenyl)methyl]-2-tri-
methylsilyloxypropanoic Acid Methyl Ester, 16b). To a
mixture of B(C6F5)3 (10 mg, 0.02 mol %) and N-(4-methoxy-
benzylidene)methanesulfonamide (213 mg, 1.0 mmol) in CH2-
Cl2 (1 mL) was added 4 (302 mg, 1.0 mmol), and then the
resulting mixture was stirred for an additional 48 h at 20 °C.
The resulting mixture was poured into 2% NaHCO3(aq), and
the organic products were extracted with CH2Cl2 (10 mL ×
5). The organic layer was washed with brine and dried over
Na2SO4. The residue was purified by silica gel column chro-
matography (n-hexane:Et2O ) 10:10) and recrystallization (n-
hexane/Et2O) to afford 16b in 15% yield as a white powder:
mp 173-175 °C; IR (KBr) 3310, 3050, 3000, 2940, 2880, 2855,
1780, 1625, 1526, 1455, 1430 cm-1; 1H NMR (300 MHz) δ 0.17
(s, 9H), 2.58 (s, 3H), 3.67 (s, 3H), 3.80 (s, 3H), 5.11 (d, J ) 9.9
Hz, 1H), 5.45 (d, J ) 9.9 Hz, 1H), 6.85 (dd, J ) 2.1 Hz, J ) 6.6
Hz, 1H), 7.20 (dd, J ) 2.1 Hz, J ) 6.6 Hz, 1H); 19F NMR (282
MHz) δ 90.0 (s, 3F); EI MS m/z (relative intensity) 428 (M+
-
15, trace), 214 (100), 134 (24), 77 (25). Anal. Calcd for C16H24F3-
NO6SSi: C, 43.33; H, 5.45; N, 3.16. Found: C, 43.41; H, 5.35;
N, 3.26.
B(C6F5)3-Catalyzed Mukaiyama Aldol Reaction of
Ketene Silyl Acetal 4 with a Ketone (3-Phenyl-2-triflu-
oromethyl-2,3-bis(trimethylsilyloxy)butyric Acid Methyl
Ester, 16c). To a mixture of B(C6F5)3 (5 mg, 0.01 mol %) and
acetophenone (120 mg, 1.0 mmol) in CH2Cl2 (1 mL) was added
4 (302 mg, 1.0 mmol), and then the resulting mixture was
stirred for an additional 48 h at 20 °C. The resulting mixture
was poured into 2% NaHCO3(aq), and the organic products
were extracted with Et2O (20 mL × 2). The organic layer was
washed with brine and dried over Na2SO4. The residue was
purified by silica gel column chromatography (n-hexane:Et2O
) 20:1) in 14% yield as a colorless oil: diastereomeric mixture
(60:40 by 19F NMR); IR (KBr) 3140, 3100, 3000, 1770, 1515,
1
1462, 1454 cm-1; H NMR (300 MHz) δ -0.04 (s, 9H, major),
0.08 (s, 9H, major), 0.11 (s, 9H, minor), 0.16 (s, 9H, minor),
1.76 (s, 3H, minor), 1.85 (q, J ) 2.1 Hz, 3H, major), 3.66 (s,
3H, major), 3.83 (s, 3H, minor), 7.23-7.46 (m, 5H × 2, major
and minor mixed); 19F NMR (282 MHz) δ 92.4 (s, 3F, minor),
92.9 (s, 3F, major); EI MS m/z (relative intensity) 363 (M+
59, trace), 193 (100), 73 (61). Anal. Calcd for C18H29F3O4Si2:
C, 51.16; H, 6.92. Found: C, 51.14; H, 7.04.
-
Acknowledgment. This work was supported by the
Ministry of Education, Culture, Sports, Science and
Technology of Japan (Grant-in-Aid for Scientific Re-
search (C), No. 17550104). We also thank the SC-NMR
1
Laboratory of Okayama University for the H and 19F
NMR analyses and the Kanto Denka Kogyo Co. Ltd. for
a generous gift of MTFP.
Supporting Information Available: 1H and 19F NMR,
IR, and MS spectral and elemental analysis data of 10a,b,
10d-f, 12a,b, 12d-h, and 15b. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO051242Q
8816 J. Org. Chem., Vol. 70, No. 22, 2005