A convenient method for the lewis base-catalyzed synthesis of α,β-unsaturated carboxylic esters using trimethylsilylketene ethyl trimethylsilyl acetal and carbonyl compounds

Article abstract of DOI:10.1246/cl.2008.704

A highly useful method for the synthesis of α,β-unsaturated carboxylic esters from various carbonyl compounds that uses trimethylsilylbetene ethyl trimethylsilyl acetal in the presence of a Lewis base catalyst such as acetate salts was established. This procedure gives the corresponding esters in high yields with excellent E stereoselectivity under mild conditions. Copyright

Full text of DOI:10.1246/cl.2008.704

704
Chemistry Letters Vol.37, No.7 (2008)
A Convenient Method for the Lewis Base-catalyzed Synthesis of ꢀ,ꢁ-Unsaturated Carboxylic
Esters Using Trimethylsilylketene Ethyl Trimethylsilyl Acetal and Carbonyl Compounds
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 April 14, 2008; CL-080383; E-mail: mukaiyam@abeam.ocn.ne.jp)
A highly useful method for the synthesis of ꢀ,ꢁ-unsaturated
O
OTMS
OEt
O
carboxylic esters from various carbonyl compounds that uses
trimethylsilylbetene ethyl trimethylsilyl acetal in the presence
of a Lewis base catalyst such as acetate salts was established.
This procedure gives the corresponding esters in high yields
with excellent E stereoselectivity under mild conditions.
Cat. Lewis Base
1
TMS
R
+
1
R2
R2
R
Aldol reaction
TMS
COOEt
1
TMSO
R2
O
1
R
OEt
syn-elimination
ꢀ,ꢁ-Unsaturated esters are the building blocks known to be
quite useful and they are frequently used in various conjugate
addition reactions such as the Michael reaction,1 the Morita–
Baylis–Hillman reaction,2 or the Diels–Alder reaction.3 In order
to prepare these ꢀ,ꢁ-unsaturated carboxylic esters, carbonyl
olefination is one of the most general and important methods.
Among the carbonyl olefination, the Wittig reaction4 is em-
ployed commonly by using phosphorous ylides. However, isola-
tion of the desired product from the co-product in this reaction is
often difficult. The Horner–Wadsworth–Emmons reaction5 and
the Peterson reaction6 are also widely used although an equimo-
lar amount of bases such as n-BuLi or NaH is required. As an
alternative method, the Knoevenagel type reaction of malonic
acid half esters with aldehydes in the presence of a catalytic
amount of DMAP is recently reported.7 While this method is
quite useful and clean for the synthesis of E-ꢀ,ꢁ-unsaturated
carboxylic ester, the substrates employed are limited to alde-
hydes, and needs long reaction time. Thus, it is required to
find more convenient ways for the synthesis of ꢀ,ꢁ-unsaturated
carboxylic esters from carbonyl compounds including ketones.
In our previous papers, it was shown that the nitrogen-
or oxygen-containing anions generated from amides, imides,
carboxylic acids, or alcohols behaved as effective Lewis-base
catalysts in the activation of trimethylsilyl (TMS) derivatives.8
In order to extend the utility, reaction of carbonyl compounds
and trimethylsilylketene ethyl trimethylsilyl acetal 1 was exam-
ined so that it may become an useful reagent for the synthesis of
ꢀ,ꢁ-unsaturated carboxylic esters. Namely, the esters would be
provided directly from aldehydes by syn elimination via the fol-
lowing aldol-type reaction. Thus, eliminated silanol anion also
works as a Lewis base, and generated TMS2O is removed easily
by evaporation (Scheme 1). In addition, the ketene acetal 1 can
easily be prepared from commercially available ethyl (trimethyl-
silyl)acetate.9 Concerning this type of reaction, Matsuda et al. re-
ported that trimethylsilylketene trimethylsilyl acetals reacted
with aldehydes to give the corresponding esters by using an
equimolar amount of Lewis acids such as AlCl3 and TiCl4.10
However, the reaction is applied only to simple aliphatic alde-
hydes and is hard to apply to the substrates having basic moiety
because the reaction is carried out under acidic conditions.
In this communication, we would like to report a convenient
method for the synthesis of ꢀ,ꢁ-unsaturated carboxylic esters
Scheme 1. Lewis base-catalyzed carbonyl olefination.
from carbonyl compounds such as aldehydes and ketones with
ketene acetal 1 under mild conditions by using a Lewis base
catalysts such as AcOLi or AcONn-Bu4.
In the first place, reactions of benzaldehyde with ketene ace-
tal 1 (E:Z = 4:1) were examined in the presence of 5 mol % each
of various Lewis bases (Table 1). The reaction did not take place
in the absence of the catalyst (Entry 1). Whereas it proceeded
smoothly to give the ca. 1:1 mixture of the corresponding E/Z
isomers in quantitative yield when AcOLi was used (Entry 2).
Then, the same reaction was tried in the different ratio of 1
and the ratios of the product remained almost unchanged
(Entry 3). These results indicate that there is no correlation
between E/Z stereoselectivity and E/Z ratio of 1.
Next, in order to investigate effects of the counter anions of
Lewis bases, lithium phenoxide was employed and the desired
product was obtained in good yield with the same ratio of iso-
mers (Entry 4). Then, effects of the counter cations were further
examined, and E stereoselectivities of the products improved as
the ionic character increased (Entries 5–8). Thus, it was noted
Table 1. Effects of Lewis bases
Catalyst
(5 mol %)
OTMS
O
O
+
Ph
H
Ph
OEt
TMS
OEt
1 (1.2 equiv)
DMF, 0 °C, 1 h
a
Entry
Catalyst
Yieldb/%
E:Zb
1
2
3
4
5
6
7
8
None
AcOLi
AcOLi
PhOLi
AcONa
AcOK
N.R.
quant.
quant.
80
98
96
—
47:53
45:55c
47:53
95:5
99:1
>99:1
>99:1
AcOCs
AcONn-Bu4
quant.
97
aUnless otherwise noted, ketene acetal 1 in a ratio of 4:1
(E:Z) was used. Yields and ratios were determined by GC
analysis using internal standard. Ketene acetal 1 in a ratio
of 1:1 (E:Z) was used.
b
c
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.7 (2008)
705
Table 2. Effects of solvents
(Entry 9). On the other hand, the reaction proceeded smoothly to
give the ca. 1:1 mixture of the desired products in high yield in
the case when AcOLi was used in DMF (Entry 10). The reaction
was also applied to aliphatic ketones such as cyclohexanone in
similar fashion (Entry 11).
AcONn-Bu4
(5 mol %)
OTMS
O
O
+
Ph
OEt
TMS
1 (1.2 equiv)a
Solv., 0 °C, 1 h
OEt
Ph
H
Thus, a convenient method for the synthesis of E-ꢀ,ꢁ-unsat-
urated carboxylic esters by using trimethylsilylketene ethyl tri-
methylsilyl acetal in the presence of a catalytic amount of
Lewis base was established. Importantly, in this procedure, only
TMS2O is formed as a co-product which is easily removed by
evaporation. This is also applied to the ketones having ꢀ-protons
as electrophiles. Further studies on this type of reactions are
now in progress.
Entry
Solv.
Yieldb/%
E:Zb
1
2
3
4
5
6c
Toluene
AcOEt
Et2O
THF
CH2Cl2
DMSO
95
84
94
quant.
quant.
92
95:5
98:2
94:6
97:3
>99:1
>99:1
aKetene acetal 1 in a ratio of 4:1 (E:Z) was used. bYields and
ratios were determined by GC analysis using internal stand-
ard. cThe reaction was carried out at room temperature.
References and Notes
1
a) J. Boyer, R. J. P. Corriu, R. Perz, C. Reye, Tetrahedron
1983, 39, 117. b) K. Ogura, H. Itoh, T. Morita, K. Sanada, H.
Iida, Bull. Chem. Soc. Jpn. 1982, 55, 1216. c) N. Duguet, A.
Harrison-Marchand, J. Maddaluno, K. Tomioka, Org. Lett.
2006, 8, 5745.
Table 3. Olefination of various carbonyl compounds
OTMS
O
AcONn-Bu
(5 mol %)
2
4
R
O
2
P. R. Krishna, M. Narsingam, P. S. Reddy, G. Srinivasulu, A. C.
Kunwar, Tetrahedron Lett. 2005, 46, 8885.
+
1
2
R
R
TMS
OEt
1
R
OEt
a
CH Cl , 0 °C, 1 h
1 (1.2 equiv)
3
4
A. Saito, H. Yanai, T. Taguchi, Tetrahedron 2004, 60, 12239.
a) M. Schlosser, K. F. Christmann, Angew. Chem., Int. Ed. Engl.
1966, 5, 126. b) F. Orsini, G. Sello, T. Fumagalli, Synlett 2006,
2
2
Entry
R1
R2 Yieldb/% E:Zc
1
2
3
4
5
6
7
8
9
2-ClC6H4
3-ClC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
Me
Me
98
94
96
>99:1
>99:1
>99:1
´
1717. c) J. P. Begue, D. B. Delpon, A. Kornilov, Org. Synth.
2004, Coll. Vol. 10, 703.
´
5
a) W. S. Wadsworth, Jr., W. D. Emmons, J. Am. Chem. Soc.
1961, 83, 1733. b) W. S. Wadsworth, Jr., W. D. Emmons, Org.
Synth. 1973, Coll. Vol. 5, 547. c) D. J. Ager, Synthesis 1984,
384. d) A. Ianni, S. R. Waldvogel, Synthesis 2006, 2103. e)
D. J. Schauer, P. Helquist, Synthesis 2006, 3654.
a) D. J. Peterson, J. Org. Chem. 1968, 33, 780. b) M. Iguchi,
K. Tomioka, Org. Lett. 2002, 4, 4329.
B. List, A. Doehring, M. T. H. Fonseca, A. Job, R. R. Torres,
Tetrahedron 2006, 62, 476.
4-MeOC6H4
quant. >99:1
4-MeO2CC6H4
4-Me2NC6H4
3-Pyridyl
c-Hex
94
92
82
72
4
>99:1
>99:1
>99:1
>99:1
>99:1
47:53
—
6
7
8
Ph
Ph
10d
11d
87
90
a) H. Fujisawa, T. Mukaiyama, Chem. Lett. 2002, 182. b) H.
Fujisawa, T. Mukaiyama, Chem. Lett. 2002, 858. c) H. Fujisawa,
T. Nakagawa, T. Mukaiyama, Adv. Synth. Catal. 2004, 346,
1241. d) T. Mukaiyama, T. Nakagawa, H. Fujisawa, Chem. Lett.
2003, 32, 56. e) T. Mukaiyama, T. Tozawa, H. Fujisawa, Chem.
Lett. 2004, 33, 1410. f) H. Fujisawa, E. Takahashi, T. Nakagawa,
T. Mukaiyama, Chem. Lett. 2003, 32, 1036. g) E. Takahashi, H.
Fujisawa, T. Mukaiyama, Chem. Lett. 2004, 33, 1426.
Ethyl C,O-bis(trimethylsilyl)ketene acetal 1 is easily prepared
in high yield by distillation as a colorless liquid: bp 55–60 ꢀC
(3.0 Torr).10
–(CH2)5–
aKetene acetal 1 in a ratio of 4:1 (E:Z) was used. bIsolated yield.
cDiastereomeric ratios were determined by 1H NMR analysis.
dThe reaction was carried out in DMF by using 5 mol % of
AcOLi.
that the suitable choice of a counter cation was crucial to obtain
the adducts in high E stereoselectivity. Next, AcONn-Bu4 was
chosen on the basis of solubility, and effect of solvents was also
examined (Table 2). It was then found that this reaction proceeds
smoothly in various solvents (Entries 1–6), and CH2Cl2 gave an
excellent result in both yield and E stereoselectivity (Entry 5).11
The observed stereoselectivity indicates that the reaction pro-
ceeds via acyclic transition states irrespective of the geometry
of the silyl enolate.
Then, reactions of various carbonyl compounds with ketene
acetal 1 were examined by using a catalytic amount of Lewis
base (Table 3). Aromatic aldehydes having electron-donating
or -withdrawing groups reacted smoothly to afford the desired
esters in high yields with complete E selectivity (Entries 1–5).
Similarly, this reaction is then applied to aldehydes having basic
moiety (Entries 6 and 7) and aliphatic aldehydes reacted smooth-
ly as well and afforded the desired adduct in good yields
(Entry 8). Next, ketones having ꢀ-protons such as acetophenone
were tried. As a result, the corresponding ester was obtained
only in poor yield and a large amount of silyl enolate was formed
9
O
OTMS
LDA, then TMSCl
TMS
OEt
THF, –78 °C
TMS
1 : 93%
E:Z = ca. 4:1
OEt
commercially
available
10 a) I. Matsuda, S. Murata, Y. Izumi, J. Org. Chem. 1980, 45, 237.
b) I. Matsuda, J. Organomet. Chem. 1987, 321, 307. c) P. Pellon,
´
Y. L. Ko, P. Cosquer, J. Hamelin, R. Carrie, Tetrahedron Lett.
1986, 27, 4299.
11 Typical experimental procedure is as follows: To a stirred solu-
tion of benzaldehyde (0.50 mmol) and trimethylsilylketene ethyl
trimethylsilyl acetal (0.60 mmol) in CH2Cl2 (2.5 mL) were added
AcONn-Bu4 (0.025 mmol) at 0 ꢀC. After the reaction mixture
was stired for 1 h, it was quenched with saturated NH4Claq.
The mixture was extracted with AcOEt and organic layer was
washed with brine, dried over anhydrous Na2SO4, and evaporat-
ed. The crude product was purified by preparative TLC to give
the desired product as a colorless oil.
Published on the web (Advance View) May 31, 2008; doi:10.1246/cl.2008.704