A convenient method for the synthesis of (Z)-α-fluoroacrylates: Lewis base-catalyzed carbonyl fluoroolefination using fluoro(trimethylsilyl)ketene ethyl trimethylsilyl acetal

Article abstract of DOI:10.1246/cl.2008.890

A highly useful method is established for the stereoselective synthesis of (Z)-α-fluoroacrylates from various aldehydes and fluoro(trimethylsilyl) ketene ethyl trimethylsilyl acetal in the presence of a Lewis base catalyst. The ketene acetal, easily prepared from ethyl fluoroacetate, affords α-fluoroacrylates in high yields with excellent Z stereoselectivities under mild conditions. Copyright

Full text of DOI:10.1246/cl.2008.890

890
Chemistry Letters Vol.37, No.8 (2008)
A Convenient Method for the Synthesis of (Z)-ꢀ-Fluoroacrylates: Lewis Base-catalyzed
Carbonyl Fluoroolefination Using Fluoro(trimethylsilyl)ketene Ethyl Trimethylsilyl Acetal
Makoto Michida1 and Teruaki MukaiyamaÃ2
1Process Technology Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-3 Kitakasai, Edogawa-ku, Tokyo 134-8630
2Center for Basic Research, Kitasato University, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
(Received June 9, 2008; CL-080573; E-mail: mukaiyam@abeam.ocn.ne.jp)
A highly useful method is established for the stereoselective
silyl (TMS) derivatives.10 More recently, trimethylsilylketene
ethyl trimethylsilyl acetal was found also as a useful reagent
for Lewis base-catalyzed carbonyl olefination in our laborato-
ry.11 To extend the utility of these reactions, stereoselective syn-
thesis of trisubstituted olefins such as ꢀ-fluoroacrylates by using
fluoro(trimethylsilyl)ketene ethyl trimethylsilyl acetal (1) was
studied. That is, the ꢀ-fluoroacrylates were formed directly from
aldehydes by syn elimination of the formed aldol intermediates
via the following Lewis base-catalyzed aldol-type reaction
(Figure 1). This reaction proceeds catalytically since the elimi-
nated silanol anion also works as a Lewis base, and the resulted
TMS2O is removed easily by evaporation. It is important to note
that ketene acetal 1 was easily prepared from commercially
available ethyl fluoroacetate in one step (Scheme 1).12
In this communication, we would like to report a convenient
method for the synthesis of (Z)-ꢀ-fluoroacrylates from carbonyl
compounds such as aldehydes and ketene acetal 1 under mild
conditions in the presence of a Lewis base catalyst.
Reactions of benzaldehyde (2a) with ketene acetal 1
(Z:E = 1:1) were tried by using 5 mol % each of various Lewis
bases (Table 1). This reaction did not take place in the absence of
synthesis of (Z)-ꢀ-fluoroacrylates from various aldehydes and
fluoro(trimethylsilyl)ketene ethyl trimethylsilyl acetal in the
presence of a Lewis base catalyst. The ketene acetal, easily pre-
pared from ethyl fluoroacetate, affords ꢀ-fluoroacrylates in high
yields with excellent Z stereoselectivities under mild conditions.
Organofluorine compounds are considered as useful build-
ing blocks for the preparation of various biologically active
compounds.1 It is well known that a fluoroolefin moiety playing
an important role as an amide isostere has unique steric and
electronic properties, which exhibits structural similarities to
the amide linkage.2 Whereas peptide bonds exist in cisoid–trans-
oid equilibrium, no isomerization occurs between E- and
Z-fluoroolefins, and they thus behave as an equivalent of amides.
Therefore, the stereoselective synthesis of fluoroolefins is impor-
tant in the area of medicinal chemistry. ꢀ-Fluoro-ꢀ,ꢁ-unsaturat-
ed carboxylic esters (ꢀ-fluoroacrylates) are frequently used as a
building block that has fluoroolefin part.3 For the stereoselective
synthesis of ꢀ-fluoroacrylates, various approaches have been in-
vestigated. Among the trials, Wittig type,4 Horner–Wadsworth–
Emmons (HWE),5 Peterson,6 and Julia type reactions7 are
widely employed even though the yields and stereoselectivities
are yet to be solved. Recently the CrII salt-mediated carbonyl
olefination reaction by using trihaloacetate was also reported
to afford (Z)-ꢀ-fluoroacrylates.8 In those reactions, however, sto-
ichiometric or excess amounts of reagents and costly fluorinated
building blocks such as BrFCHCO2Et or Br2FCCO2Et were re-
quired. While the use of in situ generated diethyl fluorooxalo-
acetate derived from ethyl fluoroacetate was also reported, yield
and stereoselectivity were still modest.9 Thus, it is desired to find
more practical and inexpensive methods.
2.2 equiv LDA
2.2 equiv TMSCl
O
TMS
F
OTMS
OEt
F
OEt
THF, −78 °C
1
Z:E = ca 1:1
Scheme 1. Preparation of ketene acetal 1.
Table 1. Optimization of reaction conditions
O
O
a
1 (1.2 equiv)
OEt
H
It was shown in our previous papers that various acetate salts
behaved as effective Lewis base catalysts to activate trimethyl-
Catalyst (5 mol %)
F
rt, 1 h
2a
3a
TMS
F
OTMS
OEt
O
Entry
Catalyst
Solvent
Yieldb/%
Z:Eb
AcOM
or
TMSOM
1
2
3
4
5
6
7
8
9
None
AcOLi
AcONa
AcOK
AcOCs
AcOn-Bu4N
AcOn-Bu4N
AcOn-Bu4N
AcOn-Bu4N
DMF
DMF
DMF
DMF
DMF
DMF
THF
Toluene
CH2Cl2
N.R.
84
84
78
87
85
86
86
96
—
R
OEt
83:17
95:5
98:2
98:2
98:2
94:6
92:8
99:1
F
AcOTMS
or
TMS2O
O
OM
OEt
TMS
F
TMS
R
H
COOEt
F
M
O
b
aKetene acetal 1 in a ratio of 1:1 (E/Z) was used. Yields
and ratios were determined by GC analysis using internal
standard.
M = Li, Na, K, Cs, n-Bu4N
R
H
Figure 1. Lewis base-catalyzed synthesis of ꢀ-fluoroacrylate.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.8 (2008)
891
Table 2. Fluoroolefination of various aldehydes
TMS
F
OTMS
OEt
H
R
R
H
TMS
TMS
O
TMSO
EtO
1 (1.2 equiv)a
AcOn-Bu4N (5 mol %)
TMSO
EtO
O
O
O
<<
<<
R
OEt
F
F
Z enolate
R
H
CH2Cl2, rt, 1 h
RCHO
F
2b−2l
3b−3l
F
OTMS
OEt
H
R
R
TMS
O
Entry
R
Product
Yieldb/%
Z:Ec
EtO
TMS
O
EtO
TMS
1
2
3
4
5
6
7
8
9
2-ClC6H4
3-ClC6H4
4-ClC6H4
3b
3c
3d
3e
3f
3g
3h
3i
94
81
93
87
95
81
93
94
77
93
53
99:1
99:1
99:1
TMSO
TMSO
F
E enolate
F
H
O
O
H
4-MeC6H4
>99:1
99:1
99:1
TMS syn-elimination
Aldol reaction
EtO
R
-
EtO
4-MeOC6H4
4-MeO2CC6H4
4-Me2NC6H4
2-Naphthyl
(E)-PhCH=CH
O
F
R
F
99:1
99:1
83:17
99:1
98:2
Scheme 2. Plausible mechanism of fluoroolefination.
3j
3k
3l
fluoroacrylates by using fluoro(trimethylsilyl)ketene ethyl tri-
methylsilyl acetal was established. In the presence of a catalytic
amount of Lewis base, this reaction proceeds smoothly in high
yield with Z selectivity. Only TMS2O was formed as a coproduct
which is easily removed by evaporation. In addition, this
procedure is useful since inexpensive ethyl fluoroacetate is used
as fluorinated building block. Further studies on this type of
reaction are now in progress.
10
11
(E)-PhCH=CMe
c-Hex
aKetene acetal 1 in a ratio of 1:1 was used. bIsolated
c
yield. Diastereomeric ratios were determined by 19F NMR
analysis.
the catalyst in DMF (Entry 1) whereas it proceeded smoothly
to give an 83:17 mixture of the corresponding Z/E isomers 3a
in 84% yield when AcOLi was used (Entry 2). Effects of the
counter cations indicate that Z stereoselectivities of the products
improved as the ionic character increased (Entries 3–6). Accord-
ingly, it is noted that the suitable choice of a counter cation was
crucial to obtain adducts with high Z stereoselectivity. Then, ef-
fect of solvents was examined by using AcOn-Bu4N on the basis
of its solubility (Entries 7–9). When CH2Cl2 was used, the best
result in yield and Z stereoselectivity (Entry 9) was obtained.
Next, reactions of various aldehydes with ketene acetal 1
were examined by using a catalytic amount of AcOn-Bu4N
(Table 2). Aromatic aldehydes having electron-donating or
-withdrawing groups reacted smoothly to afford the correspond-
ing esters 3b–3i in high yields with almost complete Z selectiv-
ity (Entries 1–8). When cinnamaldehyde (2j), an ꢀ,ꢁ-unsaturat-
ed aldehyde was used, the stereoselectivity decreased to 83:17
(Entry 9). On the other hand, in the case of ꢀ-methylcinnamal-
dehyde (2k), the corresponding diene 3k was given with excel-
lent Z selectivity (Entry 10). These results indicate that steric ef-
fects at an ꢀ-position of a carbonyl group has a great influence
on the stereoselectivity. Though the yield was moderate, the
desired product 3l was obtained with high stereoselectivity
when cyclohexanecarbaldehyde was tried (Entry 11). The above
result indicated that a silyl enolate might be formed by partial
ꢀ-proton abstraction during this aldol reaction.
The observed Z stereoselectivity shows that the first aldol
reaction proceeds via acyclic transition states irrespective of
the geometry of the ketene silyl acetal 1. As described in
Scheme 2, the reaction proceeds under steric interaction between
bulky trimethylsilyl group and R group to generate the corre-
sponding syn intermediate followed by the subsequent syn elim-
ination. In the case when AcOLi was employed, this reaction is
considered to proceed under cyclic (Li-chelated) transition state
to cause a decrease in the stereoselectivity. Further, it is noted
that the observed stereoselectivity of this reaction was opposite
to that of HWE reaction.
The authors wish to thank Ms. Takako Toriumi (Tokyo
Chemical Industry Co., Ltd.) for her support in this work.
References and Notes
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Thus, a convenient method for the synthesis of (Z)-ꢀ-
Published on the web (Advance View) July 19, 2008; doi:10.1246/cl.2008.890