A facile generation of enolates from silyl enol ethers by potassium ethoxide

Article abstract of DOI:10.1016/S0040-4039(00)01970-5

Cyclic silyl enol ethers were successfully cleaved by EtOK to generate the corresponding enolates. Reactions with EtOK were faster and the corresponding enolates could be trapped by electrophiles and oxidants to give the kinetic products exclusively.

Full text of DOI:10.1016/S0040-4039(00)01970-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 369–372
A facile generation of enolates from silyl enol ethers by
potassium ethoxide
Wensheng Yu and Zhendong Jin*
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City,
IA 52242, USA
Received 31 October 2000; accepted 6 November 2000
Abstract—Cyclic silyl enol ethers were successfully cleaved by EtOK to generate the corresponding enolates. Reactions with
EtOK were faster and the corresponding enolates could be trapped by electrophiles and oxidants to give the kinetic products
exclusively. © 2001 Elsevier Science Ltd. All rights reserved.
4
a
Generation of enolates from trimethylsilyl enol ethers
via nucleophilic cleavage is an important transforma-
available or relatively expensive.
1
2
tion in organic synthesis. Methyl lithium, lithium
In connection with a project in our laboratories, we
needed to convert silyl enol ether 1 to vinyl acetate 3
(Scheme 1). Applying the methyl lithium protocol, it
took 5 equiv. of MeLi for 8 hours at 25°C to com-
pletely convert compound 1 to its enolate 2. Several
fluoride salts were investigated, but none of them gave
satisfactory results. Therefore, we decided to develop a
new method which can easily cleave silyl enol ethers
with readily available and inexpensive reagents.
3
4
amide in ammonia, and fluoride salts have been used
in this purpose. However, limitations about these pro-
cedures still exist. The reactions employing methyl
lithium require relatively high temperature (0°C) at
which very few functionalities can tolerate its strong
nucleophilicity and basicity. The lithium amide proce-
dure requires dry ammonia which sometimes is not
convenient. ‘Dry’ fluoride salts are either not readily
Scheme 1.
Scheme 2.
Keywords: silyl enol ether; potassium alkyloxide; kinetic enolate; oxidation.
*
Corresponding author. E-mail: zhendong-jin@uiowa.edu
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01970-5

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W. Yu, Z. Jin / Tetrahedron Letters 42 (2001) 369–372
We found that the commercially available potassium
ethoxide (EtOK) is a very good reagent for this pur-
pose. The reaction of silyl enol ether 1 with 1.05 equiv.
of EtOK at 0°C afforded enolate 2 in less than 5
minutes. The enolate 2 reacted with acetyl chloride to
give the desired vinyl acetate 3 in 95% yield (Scheme 1).
When both kinetic and thermodynamic enolates can be
generated, the distinct advantage for using EtOK over
t-BuOK becomes more obvious. The majority of the
enolate was the thermodynamic enolate after com-
6
pound 4a was treated with 1 equiv. of t-BuOK at 0°C
for only 5 minutes (Table 2, entry 1). Lowering the
temperature to −50°C increased the proportion of the
kinetic enolate, but the reaction could not go to com-
pletion, and about 50% of the starting material 4a was
recovered (Table 2, entry 2). In addition, a large
amount of thermodynamic enolate was still formed
even if the reaction was kept at −78°C for 10 hours
(Table 2, entry 3). The formation of the thermodynamic
product is presumably due to the slower reaction rate
of the cleavage of silyl enol ether by t-BuOK and the
presence of the trace amount of t-BuOH in t-BuOK
which is difficult to eliminate. We were delighted to
The fast reaction between silyl enol ether 1 and EtOK
prompted us to investigate the rates of the reactions
between various alkyloxide salts and silyl enol ethers
(
Scheme 2). The results are summarized in Table 1.
5
Although both t-BuOK and EtOK converted silyl enol
ether 4a to enolate 5a at 0°C in 5 minutes (Table 1,
entries 1 and 2), the reaction with t-BuOK at −78°C
was much slower than that with EtOK (Table 1, entries
3
and 4). As expected, MeONa reacted very slowly with
silyl enol ether 4a (Table 1, entry 5). Surprisingly, the
reaction with MeOK was much slower than that with
EtOK (Table 1, entry 6). We believe that this is primar-
ily due to the very poor solubility of MeOK in THF. In
addition, EtOK completely cleaved t-butyldimethylsilyl
enol ether 4b in 10 hours at 25°C, whereas the reaction
between t-BuOK and 4b reached only 45% completion
after 24 hours (Table 1, entries 7 and 8).
7
observe that by employing EtOK, the kinetic enolate
could be successfully trapped at low temperature and
the yields and ratio were excellent (Table 2, entries 4
and 5).
The reactions between various trimethylsilyl enol ethers
with EtOK followed by in situ trapping the enolates
a
Table 1. Rates of reactions of various alkyloxide salts with cyclic silyl enol ethers
Entry
Substrates
ROM
T (°C)
Reaction time
Results
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4b
4b
t-BuOK
EtOK
t-BuOK
EtOK
MeONa
MeOK
t-BuOK
EtOK
0
0
5 minutes
5 minutes
24 hours
2.5 hours
10 hours
3 hours
Complete conversion
Complete conversion
5% Starting material left
Complete conversion
Complete conversion
Complete conversion
45% Conversion
−78
−78
25
25
25
24 hours
10 hours
25
Complete conversion
a
1
.05 equiv. of alkyloxide was used and freshly distilled THF was the reaction solvent.
Table 2. Trapping the cyclic kinetic enolate generated by t-BuOk or EtOK

W. Yu, Z. Jin / Tetrahedron Letters 42 (2001) 369–372
371
Table 3. Reactions of enolates generated from cyclic trimethylsilyl enol ethers by EtOK
Method A: EtOK (1.05 equiv.), −78°C, 2.5 h; Method B: EtOK (1.0 equiv.), 0°C, 10 minutes.
.

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W. Yu, Z. Jin / Tetrahedron Letters 42 (2001) 369–372
8
with different electrophiles are summarized in Table 3.
of Iowa. Special thanks are due to The Center for
Biocatalysis and Bioprocessing at The University of
Iowa for providing a fellowship to W.Yu.
Under our conditions, compound 11 was converted to
the enolate which reacted with Ph NTf to give vinyl
2
triflate 12 in 93% yield (Table 3, entry 1). Both silyl
enol ethers 13 and 15 were successfully converted to
vinyl phosphates in excellent yields (Table 3, entries 2
and 3). The enolates generated by our method were also
suitable for alkylation. Methylation of the enolate gen-
erated from 11 afforded monomethylated product 17 in
References
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3. Binkley, E. S.; Heathcock, C. H. J. Org. Chem. 1975, 40,
2156.
85% yield (Table 3, entry 4). Alkylation of the kinetic
enolate generated from 4a with allyl iodide and benzyl
bromide at low temperature provided monoalkylated
products 18 and 19 with the retention of the regiochem-
9
istry (Table 3, entries 5 and 6).
4. (a) Busch-Petersen, J.; Bo, Y.; Corey, E. J. Tetrahedron
Lett. 1999, 40, 2065 and references cited therein; (b)
Seppelt, K. Angew. Chem., Int. Ed. Engl. 1992, 31, 292;
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Patent 3,940,402, 1976; (g) Noyori, R.; Nishida, I.;
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1975, 97, 3257; (i) Nakamura, E.; Shimizu, M.; Kuwa-
jima, I. Tetrahedron Lett. 1976, 1699; (j) Noyori, R.;
Yokoyama, K.; Sakata, J.; Kuwajima, I.; Kuwajima, I.;
Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99,
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Am. Chem. Soc. 1982, 104, 1025; (l) Kuwajima, I.; Naka-
mura, E. Acc. Chem. Res. 1985, 18, 181.
Because the potassium enolates were prepared in the
1
0
absence of amines, the enolates generated by our
method were particularly suitable for the oxidation by
dibenzyl peroxydicarbonate developed by Vederas and
1
0a,11
his co-workers.
We found that oxidation of the
potassium enolates by dibenzyl peroxydicarbonate pro-
vided vinyl carbonates exclusively (Table 3, entries 7
and 8) or partially (Table 3, entry 9). However, we
found that the reactions could afford the carbonates of
a-hydroxy ketones exclusively simply by addition of 5
equiv. of LiBr to the potassium enolates prior to the
addition of the oxidant (Table 3, entries 10 and 11).
A typical procedure for the preparation of enolates by
EtOK from silyl enol ethers follows: 51 mg (0.61 mmol)
of EtOK was placed in a 10 mL flame dried flask under
argon. Freshly distilled THF (2 mL) was added and
then the suspension was cooled to 0°C (or −78°C for
the generation of kinetic enolate). Silyl enol ether 4a
5. (a) Duhamel, P.; Cahard, D.; Poirier, J. M. J. Chem.
Soc., Perkin Trans. 1 1993, 21, 2509; (b) Quesnel, Y.;
Bidois-Sery, L.; Poirier, J.-M.; Duhamel, L. Synlett 1998,
413.
(
112 mg, 0.61 mmol) was dissolved in 0.5 mL of freshly
distilled THF and the solution was cannulated to the
EtOK solution. The reaction was monitored by TLC.
Once silyl enol ether 4a disappeared, an electrophile or
dibenzyl peroxydicarbonate was added.
6. Solid t-BuOK, purchased from Aldrich, was vacuumed
for 12 hours before it was used in the reactions. 1.0 M
solution of t-BuOK in THF which was also purchased
from Aldrich gave the same results.
7. EtOK was purchased from Aldrich and was used directly
In conclusion, we have discovered that cyclic silyl enol
ethers can be readily cleaved by EtOK to generate the
corresponding enolates. Compared to the other
methodologies, our conditions are milder and faster.
Furthermore, it is also possible to trap the kinetic
enolates exclusively by electrophiles and oxidants under
our conditions.
without further purification.
8. All compounds were fully characterized.
9. Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989,
54, 1785. The potassium enolate was converted to the
lithium enolate by addition of 5 equiv. of lithium bro-
mide prior to addition of alkyl halide. To eliminate the
trace amount of proton in the reaction solution, 0.05
equiv. of n-BuLi was added before the addition of
lithium bromide and HMPA.
Acknowledgements
10. The presence of amines often leads to low yields in the
oxidation of enolates (a) Gore, M. P.; Vederas, J. C. J.
Org. Chem. 1986, 51, 3700; (b) Davis, F. A.; Vish-
wakarma, L. C.; Billmers, J. M. J. Org. Chem. 1984, 49,
3243.
11. One of the advantages of employing dibenzyl peroxydi-
carbonate in the oxidation of enolates is that it can avoid
the formation of the dimer of a-hydroxy ketone which
sometimes occurs in the oxidation of silyl enol ethers.
This work was supported by Grant cIN-122S from
the American Cancer Society, administered through
The University of Iowa Cancer Center, a Research
Project Grant RPG-00-030-01-CDD from the Ameri-
can Cancer Society, and the Central Investment Fund
for Research Enhancement (CIFRE) at The University
.
.