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]

The general structure of a silyl enol ether

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 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.

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 S_N1-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 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.

Halogenation and oxidations

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

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.

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.

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.

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.