Lewis acid promoted aldol reaction of fluorinated silyl enol ethers from new fluoroacetylsilane derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.05.055

New fluorinated silyl enol ethers with various trialkylsilyl groups were synthesized. Various fluorinated β-hydroxy ketones were synthesized by Lewis acid promoted aldol reaction of silyl enol ethers with diverse aldehydes. Reactivity of various trialkyls

Full text of DOI:10.1016/j.tetlet.2004.05.055

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5403–5406
Lewis acid promoted aldol reaction of fluorinated silyl enol ethers
from new fluoroacetylsilane derivativesq
Woo Jin Chung, Silvana C. Ngo, Seiichiro Higashiya and John T. Welch*
Department of Chemistry, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222, USA
Received 8 January 2004; accepted 13 May 2004
Abstract—New fluorinated silyl enol ethers with various trialkylsilyl groups were synthesized. Various fluorinated b-hydroxy
ketones were synthesized by Lewis acid promoted aldol reaction of silyl enol ethers with diverse aldehydes. Reactivity of various
trialkylsilyloxy groups toward Lewis acid was also studied.
Ó 2004 Elsevier Ltd. All rights reserved.
The introduction of fluorine into organic molecules has
been a subject of interest in organic and medicinal
chemistry due to the improved or unexpected properties
imparted by fluorine.1 For example, fluorinated ketones
that contain fluorinated carbons alpha to the carbonyl
groupand promote the formation of stable hydrates
may act as inhibitors of proteases and esterases. These
stable hydrates mimic the transition state involved in
amide and ester hydrolysis.2 Silyl enol ethers, widely
used in carbon–carbon bond formation because of their
high reactivity and ready availability can also be rec-
ognized as precursors for the formation of a-fluorinated
ketones.3 Various aldol reactions have been effected with
difluoroenol ethers prepared from ethyl a-chloro-a,a-
difluoroacetate,4 difluoroketene silyl acetals,5 and diflu-
orosilyl enol ethers.6–9 Precedence for the preparation of
difluorosilyl enol ethers has been reported. Several of the
known preparative methods for the synthesis of these
compounds involve reductive trimethylsilylation using
metals such as zinc with chlorodifluoroketones6 or
magnesium with trifluoroketones7 in the presence of
chlorotrimethylsilane. Alternative approaches require
the electrophilic reaction of silylketones with trifluoro-
methyltrimethylsilane8 or nucleophilic addition of
organometallic reagents to trifluoroacetylsilanes.9
Recently, we reported the facile preparation of mono-
and difluorinated acetyltrialkylsilanes 2, 3, and the silyl
enol ethers 1 from 2,2,2-trifluoroethanol in the presence
of chlorotrialkylsilanes and LDA (Scheme 1).10 These
fluorinated acetylsilane derivatives, synthetic equivalents
of hindered aldehydes, react with nucleophiles under
basic conditions to give Brook isomerized products,
which are normally not obtainable from the corre-
sponding aldehydes (Scheme 2).11 Furthermore, reac-
tions with electrophiles give a-substituted products
preserving the fluoroacylsilanes functionality. Explora-
tion of the reactions of this class of compounds can be
expected to expand organofluorosilicon chemistry and
open pathways to the preparation of various materials
with medicinal and materials applications.
In this letter, we wish to present the results of our
continuing studies on the development of new fluori-
nated building blocks and their synthetic utility,
including nucleophilic modification on the a-carbons.
Keywords: Fluorinated ketone; Aldol reaction; Lewis acid; Fluorinated
silyl enol ether.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.05.055
* Corresponding author. Tel.: +1-518-442-4455; fax: +1-518-442-3462;
e-mail: jwelch@uamail.albany.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.055

5404
W.J.Chung et al./ Tetrahedron Letters 45 (2004) 5403–5406
Table 2. Formation of b-hydroxy-a,a-difluorotriphenylsilylketones 5
from 1a and various aldehydes12
5
R
Yield (%)a
84
19F NMR of 5
)109.5 (dd),
)119.4 (dd)
5a
O2N
)110.5 (dd),
)119.3 (dd)
5b
5c
80
82
Scheme 2.
Cl
Initially the utility of these compounds in the aldol
condensation was demonstrated with compound 1
employing benzaldehyde as substrate. The TiCl4 pro-
moted aldol condensation reaction of 1e at room tem-
perature gave the desired product (either little or no
aldol product was obtained at lower temperatures, )78
and 0 °C). Under optimized reaction conditions, various
b-hydroxy-a,a-difluorotrialkylsilylketones 4 were syn-
thesized in good yields. The influence of substituents on
the 2-trialkylsilyl groups (R) was seemingly limited. In
contrast, variation of the substituents on the 2-trialkyl-
silyloxyl groups (R0) dramatically affected the reactivity.
For example, reactions of triphenylsilylenol ether 1f
with TiCl4 and BCl3 did not give the desired aldol
product 4a even with longer reaction times at room
temperature, while the InCl3 promoted reactions of 1f
and 1g proceeded more slowly than the corresponding
trimethylsilylenol ethers but did form 4a and 4f,
respectively, in good yields (Table 1).
63.2 (s)
)109.8 (dd),
)119.6 (dd)
F3C
)110.3 (dd),
)118.5 (dd)
5d
5e
72
74
)110.0 (dd),
)120.2 (dd)
H3C
107.2 (dd),
)121.5 (dd)
5f
58
68
5g
)106.1(dd),
)122.0 (dd)
NO2
CH3
5h
59
)107.6 (dd),
)121.8 (dd)
The generality of the reaction of compound 1a was
explored further with various aldehydes. As summarized
in Table 2, the desired b-hydroxy-a,a-difluoro-
triphenylsilylketones 5 were obtained in good yields. As
expected, aromatic aldehydes 5a–h gave better yields
than aliphatic aldehydes 5i–j. The presence of electron
withdrawing groups on the aromatic rings generally re-
sulted in higher yields in contrast to those aromatic
moieties with electron donating groups. Aldehydes with
5i
5j
45
42
)111.5 (dd),
)120.0 (dd)
Et
)111.3 (dd),
)122.4 (dd)
a Isolated yield and characterized by 1H, 13C, and 19F NMR.
Table 1. Formation of b-hydroxy-a,a-difluorotrialkylsilylketones 4
1
SiR3
SiR03
Lewis acid
Conditions
4
Yield (%)a 19F NMR of 4
1a
1b
1c
1d
1e
1f
TPS (triphenylsilyl)
TES (triethylsilyl)
TMS
TMS
TBDMS (t-butyldimethylsilyl) TMS
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
InCl3
InCl3
0 °C to rt, 1 h
0 °C to rt, 1 h
0 °C to rt, 1 h
0 °C to rt, 1 h
0 °C to rt, 1 h
rt, 2 d
4a
4b
4c
4d
4e
4a
4f
82
71
78
76
75
73
63
)109.6 (dd), )120.4 (dd)
)112.2 (dd), )122.8 (dd)
)112.4 (dd), )121.2 (dd)
)109.6 (dd), )121.2 (dd)
)110.5 (dd), )123.6 (dd)
)109.6 (dd), )120.4 (dd)
)112.3 (dd), )121.3 (dd)
TBDPS (t-butyldiphenylsilyl)
TIPS (triisopropyl)
TPS
TMS
TMS
TPS
1g
TMS (trimethylsilyl)
TPS
rt, 2 d
a Isolated yield and characterized by 1H, 13C, and 19F NMR.

W.J.Chung et al./ Tetrahedron Letters 45 (2004) 5403–5406
Table 3. Aldol reaction of mono-and difluorinated silyl enol ethers 6, 713
5405
6, 7
SiR3
TES
R2
Ph
Lewis acid
BCl3
Conditions
rt, 2 h
Yield of 8+9 (%)a 19F NMR of 8
19F NMR of 9
6a
44 (8a+9a)
)128.0 (dd)
)128.0 (dd)
)126.6 (d)
)126.5 (d)
6a
TES
TES
TES
BCl3
rt, 2 h
37 (8b+9b)
H3C
F3C
O2N
6a
6a
6a
BCl3
BCl3
BCl3
rt, 2 h
rt, 2 h
rt, 2 h
41 (8c+9c)
48 (8d)
)63.3 (s),
)128.0 (dd)
)63.6 (s)
)126.6 (d)
)127.8 (dd)
––
TES
66 (8e+9e)
)127.9 (dd)
)126.5 (d)
7b
7c
TIPS Ph
TBDPS Ph
TiCl4
TiCl4
rt, 24 h
rt, 24 h
57 (8f+9f)
47 (8f+9f)
)228.4 (t)
)228.4 (t)
)229.2 (t)
)229.2 (t)
a Isolated yield and characterized by 1H, 13C, and 19F NMR.
hetero atom-bearing substituents such as anisaldehyde
and dimethylaminobenzaldehyde are not compatible
with Lewis acids promoted reaction and gave no aldol
product. Products obtained from aromatic aldehydes
were solids easily purified by recrystallization in hexane,
while aldol products from aliphatic aldehydes were
purified by silica gel column chromatography.
aldehydes, which gave the aldol product exclusively.
Effects of substituents on silyl groupshowed that
reactions with sterically hindered silyl substituents
required longer reaction times and careful choice of
Lewis acid.
Acknowledgements
The Mukaiyama aldol reaction of di and mono-fluoro-
silyl enol ethers 6 and 7,11 prepared from the corre-
Financial support of this work by National Institutes of
Health Grant Number AI40972 is gratefully acknowl-
edged.
sponding
fluoroacetyltrialkylsilanes
2
and
3,
respectively, with dimethylsulfoxonium methylide by
means of Brook isomerization, was explored. Results
with TiCl4 as Lewis acid (Table 3) showed that those
molecules with sterically demanding silyl substituents
are remarkably unreactive. Similar results were observed
with other Lewis acids such as TaCl5, SbF5, BF3ÆEt2O,
and TMSOTf. Use of BCl3 with 6a gave b-hydroxy
ketones 8 as the major products with small amounts of
a,b-unsaturated ketones 9. However, spontaneous
dehydration occurred on chromatographic purification
forming 9 as the major products. For the mono-fluori-
nated silyl enol ethers 7, TiCl4 promoted the aldol
reaction. As in the difluoro cases, concomitant dehy-
dration occurred on purification.
References and notes
1. (a) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; American Chemical
Society: Washington, DC, 1996; (b) Fluorine in Bioorganic
Chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; John
Wiley and Sons: New York, 1991; (c) Tozer, M. J.;
Herpin, T. F. Tetrahedron 1996, 52, 8619; (d) Percy, J. M.
Top.Curr.Chem. 1997, 193, 131.
2. Altenburger, J. M.; Schirlin, D. Tetrahedron Lett. 1991,
32, 7255.
3. (a) Mukaiyama, T.; Kobayashi, S. Org.React. 1994, 46, 1;
(b) Bednarski, M. D.; Lyssikatos, J. P. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, Chapter 2.5.
4. Kodama, Y.; Yamane, H.; Okumura, M.; Shiro, M.;
Taguchi, T. Tetrahedron 1995, 51, 12217.
5. Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishi-
moto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 10271.
6. Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett.
1983, 24, 507.
7. (a) Amii, H.; Kobayashi, T.; Hatamoto, T.; Uneyama, K.
J.Chem.Soc,. Chem.Commun. 1999, 1323; (b) Uneyama,
K.; Amii, H. J.Fluorine Chem. 2002, 114, 127.
In summary, Lewis acid promoted aldol reactions of
two different fluorinated silyl enol ethers were studied.
Reactions with 1,1-difluoro-2-trialkylsilyl-2-trialkylsilyl-
oxyethenes 1 gave various b-hydroxy-a,a-difluoro-
trialkylsilylketones 4 and 5 in good to moderate yields.
Aldol reactions of compounds 6 and 7 gave b-hydroxy
ketones 8 as the major products but dehydration during
purification resulted in the formation of a,b-unsaturated
ketones 9 except for the nitro-substituted aromatic

5406
W.J.Chung et al./ Tetrahedron Letters 45 (2004) 5403–5406
8. (a) Brigaud, T.; Doussot, P.; Portella, C. J.Chem.Soc,.
Chem.Commun. 1994, 2117; (b) Lefebvre, O.; Brigaud, T.;
Portella, C. J.Org.Chem. 2001, 66, 1941.
9. (a) Jin, F.; Jiang, B.; Hu, Y. Tetrahedron Lett. 1992, 33,
1221; (b) Jin, F.; Hu, Y.; Huang, W. J.Chem.Soc,. Chem.
Commun. 1993, 814; (c) Jin, F.; Hu, Y.; Huang, W.
J.Chem.Soc,. Perkin Trans. 1993, 795.
10. Higashiya, S.; Lim, D. S.; Ngo, S. C.; Toscano, P. J.;
Welch, J. T. Abstract of Paper, 222nd National Meeting of
the American Chemical Society, Chicago, IL, 2001;
American Chemical Society: Washington, DC, ORGN 41.
11. Ngo, S. C.; Chung, W. C.; Lim, D. S.; Higashiya, S.;
Welch, J. T. J.Fluorine Chem. 2002, 117, 207.
12. Typical procedure for 4 and 5: To a mixture of aldehyde
(0.8 mmol) and TiCl4 (1 mmol, 189 mg) in 3 mL of dichlo-
romethane was added a solution of compound 1a (1 mmol,
410 mg) in 2 mL of dichloromethane at 0 °C. The resulting
mixture was stirred at room temperature for 1 h. Reaction
mixture was quenched by the addition of saturated NaHCO3
solution, and then extracted with dichloromethane. The
organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated. Product 5 was purified by
recrystallization in hexane or silica gel column chromato-
graphy using a mixture of hexane and ethyl acetate (30:1 v/v).
13. Typical procedure for 8 and 9: Lewis acid (2 equiv) was
added to a solution of the aldehyde in dichloromethane at
0 °C. The silyl enol ethers 6 or 7 were added and the
mixture allowed to warm to room temperature. After 2–
3 h, the reaction mixture was quenched with saturated
NaHCO3 solution and extracted with dichloromethane.
The combined organic portions were dried over MgSO4,
filtered, and concentrated. Purification via silica gel
column chromatography afforded the spectroscopically
pure products 8 and 9.