Silyl enol ether

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The general structure of a silyl enol ether Silyl enol ether.png
The general structure of a silyl enol ether

In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group R3Si−O−CR=CR2, composed of an enolate (R3C−O−R) bonded to a silane (SiR4) through its oxygen end and an ethene group (R2C=CR2) as its carbon end. They are important intermediates in organic synthesis. [1] [2]

Contents

Synthesis

Silyl enol ethers are generally prepared by reacting an enolizable carbonyl compound with a silyl electrophile and a base, or just reacting an enolate with a silyl electrophile. [3] Since silyl electrophiles are hard and silicon-oxygen bonds are very strong, the oxygen (of the carbonyl compound or enolate) acts as the nucleophile to form a Si-O single bond. [3]

The most commonly used silyl electrophile is trimethylsilyl chloride. [3] To increase the rate of reaction, trimethylsilyl triflate may also be used in the place of trimethylsilyl chloride as a more electrophilic substrate. [4] [5]

When using an unsymmetrical enolizable carbonyl compound as a substrate, the choice of reaction conditions can help control whether the kinetic or thermodynamic silyl enol ether is preferentially formed. [6] For instance, when using lithium diisopropylamide (LDA), a strong and sterically hindered base, at low temperature (e.g., -78°C), the kinetic silyl enol ether (with a less substituted double bond) preferentially forms due to sterics. [6] [7] When using triethylamine , a weak base, the thermodynamic silyl enol ether (with a more substituted double bond) is preferred. [6] [8] [9]

Example synthesis of a kinetic silyl enol ether by reacting an unsymmetrical ketone with trimethylsilyl chloride and LDA at low temperature. Example synthesis of a kinetic silyl enol ether.png
Example synthesis of a kinetic silyl enol ether by reacting an unsymmetrical ketone with trimethylsilyl chloride and LDA at low temperature.
Example synthesis of a thermodynamic silyl enol ether by reacting an unsymmetrical ketone with trimethylsilyl chloride and triethylamine. Two possible mechanisms are shown. Example synthesis of a thermodynamic silyl enol ether.png
Example synthesis of a thermodynamic silyl enol ether by reacting an unsymmetrical ketone with trimethylsilyl chloride and triethylamine. Two possible mechanisms are shown.

Alternatively, a rather exotic way of generating silyl enol ethers is via the Brook rearrangement of appropriate substrates. [10]

Reactions

General reaction profile

Silyl enol ethers are neutral, mild nucleophiles (milder than enamines) that react with good electrophiles such as aldehydes (with Lewis acid catalysis) and carbocations. [11] [12] [13] [14] Silyl enol ethers are stable enough to be isolated, but are usually used immediately after synthesis. [11]

Generation of lithium enolate

Lithium enolates, one of the precursors to silyl enol ethers, [6] [7] can also be generated from silyl enol ethers using methyllithium. [15] [3] The reaction occurs via nucleophilic substitution at the silicon of the silyl enol ether, producing the lithium enolate and tetramethylsilane. [15] [3]

Generation of a lithium enolate from a silyl enol ether, using methyllithium. Lithium enolate synthesis.png
Generation of a lithium enolate from a silyl enol ether, using methyllithium.

C–C bond formation

Silyl enol ethers are used in many reactions resulting in alkylation, e.g., Mukaiyama aldol addition, Michael reactions, and Lewis-acid-catalyzed reactions with SN1-reactive electrophiles (e.g., tertiary, allylic, or benzylic alkyl halides). [16] [17] [18] [13] [12] Alkylation of silyl enol ethers is especially efficient with tertiary alkyl halides, which form stable carbocations in the presence of Lewis acids like TiCl4 or SnCl4. [12]

Example alkylation of a silyl enol ether using a tertiary alkyl halide in the presence of the Lewis acid
TiCl4. Example alkylation reaction with a silyl enol ether.png
Example alkylation of a silyl enol ether using a tertiary alkyl halide in the presence of the Lewis acid TiCl4.
Example Michael reaction using a disubstituted enone and the silyl enol ether of acetophenone, catalyzed by the Lewis acid
TiCl4 at low temperature. Michael reaction with silyl enol ether.png
Example Michael reaction using a disubstituted enone and the silyl enol ether of acetophenone, catalyzed by the Lewis acid TiCl4 at low temperature.
More example reactions of silyl enol ethers. Sienolrxns.png
More example reactions of silyl enol ethers.

Halogenation and oxidations

Halogenation of silyl enol ethers gives haloketones. [19] [20]

Example halogenation of a silyl enol ether. Halogenation.png
Example halogenation of a silyl enol ether.

Acyloins form upon organic oxidation with an electrophilic source of oxygen such as an oxaziridine or mCPBA. [21]

In the Saegusa–Ito oxidation, certain silyl enol ethers are oxidized to enones with palladium(II) acetate.

Saegusa Acyclic.svg

Sulfenylation

Reacting a silyl enol ether with PhSCl, a good and soft electrophile, provides a carbonyl compound sulfenylated at an alpha carbon. [22] [20] In this reaction, the trimethylsilyl group of the silyl enol ether is removed by the chloride ion released from the PhSCl upon attack of its electrophilic sulfur atom. [20]

Example sulfenylation of a silyl enol ether. Sulfenylation.png
Example sulfenylation of a silyl enol ether.

Hydrolysis

Hydrolysis of a silyl enol ether results in the formation of a carbonyl compound and a disiloxane. [23] [24] In this reaction, water acts as an oxygen nucleophile and attacks the silicon of the silyl enol ether. [23] This leads to the formation of the carbonyl compound and a trimethylsilanol intermediate that undergoes nucleophilic substitution at silicon (by another trimethylsilanol) to give the disiloxane. [23]

Example hydrolysis of a silyl enol ether to give a carbonyl compound and hexamethyldisiloxane. Silyl enol ether hydrolysis.png
Example hydrolysis of a silyl enol ether to give a carbonyl compound and hexamethyldisiloxane.

Ring contraction

Cyclic silyl enol ethers undergo regiocontrolled one-carbon ring contractions. [25] [26] These reactions employ electron-deficient sulfonyl azides, which undergo chemoselective, uncatalyzed [3+2] cycloaddition to the silyl enol ether, followed by loss of dinitrogen, and alkyl migration to give ring-contracted products in good yield. These reactions may be directed by substrate stereochemistry, giving rise to stereoselective ring-contracted product formation.

Silyl ketene acetals

Silyl enol ethers of esters (−OR) or carboxylic acids (−COOH) are called silyl ketene acetals [13] and have the general structure R3Si−O−C(OR)=CR2. These compounds are more nucleophilic than the silyl enol ethers of ketones (>C=O). [13]

General structure of a silyl ketene acetal. Silyl ketene acetal.png
General structure of a silyl ketene acetal.

Related Research Articles

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<span class="mw-page-title-main">Aldol reaction</span> Chemical reaction

The aldol reaction is a reaction in organic chemistry that combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. Its simplest form might involve the nucleophilic addition of an enolized ketone to another:

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<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

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<span class="mw-page-title-main">Enol</span> Organic compound with a C=C–OH group

In organic chemistry, alkenols are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene (olefin) with a hydroxyl group attached to one end of the alkene double bond. The terms enol and alkenol are portmanteaus deriving from "-ene"/"alkene" and the "-ol" suffix indicating the hydroxyl group of alcohols, dropping the terminal "-e" of the first term. Generation of enols often involves deprotonation at the α position to the carbonyl group—i.e., removal of the hydrogen atom there as a proton H+. When this proton is not returned at the end of the stepwise process, the result is an anion termed an enolate. The enolate structures shown are schematic; a more modern representation considers the molecular orbitals that are formed and occupied by electrons in the enolate. Similarly, generation of the enol often is accompanied by "trapping" or masking of the hydroxy group as an ether, such as a silyl enol ether.

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<span class="mw-page-title-main">Enolate</span> Organic anion formed by deprotonating a carbonyl (>C=O) compound

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<span class="mw-page-title-main">Trimethylsilyl group</span> Functional group

A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si(CH3)3], which is in turn bonded to the rest of a molecule. This structural group is characterized by chemical inertness and a large molecular volume, which makes it useful in a number of applications.

<span class="mw-page-title-main">Trimethylsilyl chloride</span> Organosilicon compound with the formula (CH3)3SiCl

Trimethylsilyl chloride, also known as chlorotrimethylsilane is an organosilicon compound, with the formula (CH3)3SiCl, often abbreviated Me3SiCl or TMSCl. It is a colourless volatile liquid that is stable in the absence of water. It is widely used in organic chemistry.

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<span class="mw-page-title-main">Mukaiyama aldol addition</span> Organic reaction between a silyl enol ether and an aldehyde or formate

In organic chemistry, the Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde or formate. The reaction was discovered by Teruaki Mukaiyama in 1973. His choice of reactants allows for a crossed aldol reaction between an aldehyde and a ketone, or a different aldehyde without self-condensation of the aldehyde. For this reason the reaction is used extensively in organic synthesis.

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<span class="mw-page-title-main">Teruaki Mukaiyama</span> Japanese chemist (1927–2018)

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