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Silyl enol ether

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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]

Synthesis

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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

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General reaction profile

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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

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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

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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 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

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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.

Saegusa oxidation

Sulfenylation

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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

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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

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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

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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.

References

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  1. ^ Peter Brownbridge (1983). "Silyl Enol Ethers in Synthesis - Part I". Synthesis. 1983: 1–28. doi:10.1055/s-1983-30204.
  2. ^ Ian Fleming (2007). "A Primer on Organosilicon Chemistry". Ciba Foundation Symposium 121 - Silicon Biochemistry. Novartis Foundation Symposia. Vol. 121. Wiley. pp. 112–122. doi:10.1002/9780470513323.ch7. ISBN 978-0-470-51332-3. PMID 3743226.
  3. ^ a b c d e Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers. In Organic chemistry (Second ed., pp. 466-467). Oxford University Press.
  4. ^ Clayden, J., Greeves, N., & Warren, S. (2012). Nucleophilic substitution at silicon. In Organic chemistry (Second ed., pp. 669-670). Oxford University Press.
  5. ^ Jung, M. E., & Perez, F. (2009). Synthesis of 2-Substituted 7-Hydroxybenzofuran-4-carboxylates via Addition of Silyl Enol Ethers to o -Benzoquinone Esters. Organic Letters, 11(10), 2165–2167. doi:10.1021/ol900416x
  6. ^ a b c d Chan, T.-H. (1991). Formation and Addition Reactions of Enol Ethers. In Comprehensive Organic Synthesis (pp. 595–628). Elsevier. doi:10.1016/B978-0-08-052349-1.00042-1
  7. ^ a b Clayden, J., Greeves, N., & Warren, S. (2012). Kinetically controlled enolate formation. In Organic chemistry (Second ed., pp. 600-601). Oxford University Press.
  8. ^ Clayden, J., Greeves, N., & Warren, S. (2012). Thermodynamically controlled enolate formation. In Organic chemistry (Second ed., pp. 599-600). Oxford University Press.
  9. ^ Clayden, J., Greeves, N., & Warren, S. (2012). Making the more substituted enolate equivalent: thermodynamic enolates. In Organic chemistry (Second ed., p. 636). Oxford University Press.
  10. ^ Clive, Derrick L. J. & Sunasee, Rajesh (2007). "Formation of Benzo-Fused Carbocycles by Formal Radical Cyclization onto an Aromatic Ring". Org. Lett. 9 (14): 2677–2680. doi:10.1021/ol070849l. PMID 17559217.
  11. ^ a b Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers in aldol reactions. In Organic chemistry (Second ed., pp. 626-627). Oxford University Press.
  12. ^ a b c Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers are alkylated by SN1-reactive electrophiles in the presence of Lewis acid. In Organic chemistry (Second ed., p. 595). Oxford University Press.
  13. ^ a b c d Clayden, J., Greeves, N., & Warren, S. (2012). Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product. In Organic chemistry (Second ed., pp. 608-609). Oxford University Press.
  14. ^ Quirk, R.P., & Pickel, D.L. (2012). Silyl enol ethers. In Controlled end-group functionalization (including telechelics) (pp. 405-406). Elsevier. doi:10.1016/B978-0-444-53349-4.00168-0
  15. ^ a b House, H. O., Gall, M., & Olmstead, H. D. (1971). Chemistry of carbanions. XIX. Alkylation of enolates from unsymmetrical ketones. The Journal of Organic Chemistry, 36(16), 2361–2371. doi:10.1021/jo00815a037
  16. ^ Matsuo, J., & Murakami, M. (2013). The Mukaiyama Aldol Reaction: 40 Years of Continuous Development. Angewandte Chemie International Edition, 52(35), 9109–9118. doi:10.1002/anie.201303192
  17. ^ Narasaka, K., Soai, K., Aikawa, Y., & Mukaiyama, T. (1976). The Michael Reaction of Silyl Enol Ethers with α, β-Unsaturated Eetones and Acetals in the Presence of Titanium Tetraalkoxide and Titanium Tetrachloride. Bulletin of the Chemical Society of Japan, 49(3), 779-783. doi:10.1246/bcsj.49.779
  18. ^ M. T. Reetz & A. Giannis (1981) Lewis Acid Mediated α-Thioalkylation of Ketones, Synthetic Communications, 11:4, 315-322, doi:10.1080/00397918108063611
  19. ^ Teruo Umemoto; Kyoichi Tomita; Kosuke Kawada (1990). "N-Fluoropyridinium Triflate: An Electrophilic Fluorinating Agent". Organic Syntheses. 69: 129. doi:10.1002/0471264180.os069.16. ISBN 0-471-26422-9.
  20. ^ a b c Clayden, J., Greeves, N., & Warren, S. (2012). Reactions of silyl enol ethers with halogen and sulfur electrophiles. In Organic chemistry (Second ed., pp. 469-470). Oxford University Press.
  21. ^ Organic Syntheses, Coll. Vol. 7, p.282 (1990); Vol. 64, p.118 (1986) Article.
  22. ^ Chibale, K., & Warren, S. (1996). Kinetic resolution in asymmetric anti aldol reactions of branched and straight chain racemic 2-phenylsulfanyl aldehydes: asymmetric synthesis of cyclic ethers and lactones by phenylsulfanyl migration. Journal of the Chemical Society, Perkin Transactions 1, (16), 1935-1940. doi:10.1039/P19960001935
  23. ^ a b c Clayden, J., Greeves, N., & Warren, S. (2012). Hydrolysis of enol ethers. In Organic chemistry (Second ed., pp. 468-469). Oxford University Press.
  24. ^ Gupta, S. K., Sargent, J. R., & Weber, W. P. (2002). Synthesis and photo-oxidative degradation of 2, 6-bis-[ω-trimethylsiloxypolydimethylsiloxy-2′-dimethylsilylethyl] acetophenone. Polymer, 43(1), 29-35. doi:10.1016/S0032-3861(01)00602-4
  25. ^ (a) Wohl, R. Helv. Chim. Acta 1973, 56, 1826. (b) Xu, Y. Xu, G.; Zhu, G.; Jia, Y.; Huang, Q. J. Fluorine Chem. 1999, 96, 79.
  26. ^ Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634.
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