Ethyl Trimethylsilylacetate1

[4071-88-9]  · C7H16O2Si  · Ethyl Trimethylsilylacetate  · (MW 160.29)

(silylating agent;2 source of an ethyl acetate anion equivalent3)

Alternate Name: ETSA.

Physical Data: bp 157-158 °C; d 0.876 g cm-3.

Solubility: sol ethereal and chlorinated solvents; reacts with protic solvents.

Form Supplied in: liquid (>98%); commercially available.

Preparative Methods: available by a Reformatsky reaction from ethyl bromoacetate,4 and by reaction of Trimethylsilylmethylmagnesium Chloride with Ethyl Chloroformate.5 An alternative approach requires the treatment of ethyl acetate with triphenylmethylsodium followed by Chlorotrimethylsilane.6 The use of a nitrogen base with ethyl acetate in THF followed by reaction with chlorotrimethylsilane results in a mixture of C- and O-silylation. The use of HMPA as additive in the reaction medium increases the amount of O-silylation to 90%.7 Similar methods can be used to prepare analogs.

Handling, Storage, and Precautions: reacts with protic solvents to give the desilylated product.

Ethyl trimethylsilylacetate (1) is reactive to nucleophiles and readily undergoes desilylation reactions with acid or alkali, ethanol, and bromine (eq 1).5,8

Silylation Reactions.

In the presence of a catalytic amount of Tetra-n-butylammonium Fluoride (TBAF), ester (1) is a very efficient silylating agent for a wide variety of substrates including carbonyl compounds, alcohols, phenols, carboxylic acids, and alkynes.2,9 With unsymmetrical ketones the kinetic enol ether is the preferred product.2,10 Indeed, the use of (1) can provide superior selectivity to the use of hindered bases for enolate formation.11 This is illustrated with a b,g-epoxy ester which provides an entry to g-keto-a,b-unsaturated esters (eq 2).12 These silylation reactions of (1) can also be catalyzed by TBAF supported on silica.13

Alkylation Reactions.

The use of fluoride ion or a base catalyst allows reaction of the silyl ester (1) with electrophilic substrates (eq 3). Some of these reactions are similar to those of the ester enolate derived from ethyl acetate.3,14,15

With conjugated enones a carbon-carbon bond is formed by a Michael addition with concomitant formation of the proximal silyl enol ether (eq 4).16 In the presence of a Lewis acid, (1) undergoes conjugate additions with a,b-unsaturated carbonyl compounds (eq 5).17

Nitroaromatic compounds react with (1) in the presence of Potassium Fluoride to provide an anionic s-complex.18 Subsequent oxidation with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone then provides ethyl arylacetates.19 With an areneiron(I) complex, the alkylcarbonyl substituent from (1) is introduced on to the ring.20

Electrophilic Reactions.

Silylacetate (1) reacts with 2 equiv of a Grignard reagent to provide 1,1-disubstituted alkenes in good to excellent yield (eq 6), but this synthesis is limited to Grignard reagents that are not sterically demanding.21

Analogs.

The methyl ester (2) undergoes similar reactions to the ethyl ester (1),22 as do various silyl analogs.23 These reactions also include silylations with methyl trimethylsilylacetate in the presence of fluoride ion.24,25

Reaction of the lithium enolate of (1) followed by reaction with chlorotrimethylsilane provides ketene acetal (3). This enol reacts with aldehydes in the presence of a Lewis acid to provide (Z)-a,b-unsaturated esters (eq 7).26 With conjugated enones, (3) undergoes conjugate addition when Titanium(IV) Chloride is used as catalyst (cf. eq 5).27

The use of ethyl diphenylmethylsilylacetate (4; R1 = H) provides for some alternative methodology as the larger silyl group allows for the selective addition of only 1 equiv of Grignard reagent to afford the b-silyl ketone (eq 8).28 The chemistry can also be extended to other carboxylic acid analogs. A number of approaches are then available for the preparation of ketones.22,29,30

In addition to these enolate reactions, b-silyl ketones can be thermally isomerized to silyl enol ethers by a regioselective rearrangement (eq 9),22,31 or treated with another Grignard reagent to provide alkenes through Peterson alkenation reactions.32

Many of the reactions of ethyl trimethylsilylacetate and its analogues involve the ester enolate; these are discussed in Ethyl Lithio(trimethylsilyl)acetate.

Related Reagents.

t-Butyl a-Lithiobis(trimethylsilyl)acetate; t-Butyl Trimethylsilylacetate; Dilithioacetate; Ethyl Bromozincacetate; Ethyl Lithioacetate; Ethyl Lithio(trimethylsilyl)acetate; Ketene Bis(trimethylsilyl) Acetal; Ketene t-Butyldimethylsilyl Methyl Acetal; 1-Methoxy-2-trimethylsilyl-1-(trimethylsilyloxy)ethylene; Methyl (Methyldiphenylsilyl)acetate; Trimethylsilylacetic Acid.


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23. Cruz de Maldonado, V.; Larson, G. L. SC 1983, 13, 1163.
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25. Sugimura, T.; Paquette, L. A. JACS 1987, 109, 3017.
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31. Brook, A. G. ACR 1974, 7, 77.
32. Hernández, D.; Larson, G. L. JOC 1984, 49, 4285.

David J. Ager

The NutraSweet Company, Mount Prospect, IL, USA



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