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Silyl enol ether
Class of organic compounds

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.

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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.4

The most commonly used silyl electrophile is trimethylsilyl chloride.5 To increase the rate of reaction, trimethylsilyl triflate may also be used in the place of trimethylsilyl chloride as a more electrophilic substrate.67

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.8 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.910 When using triethylamine, a weak base, the thermodynamic silyl enol ether (with a more substituted double bond) is preferred.111213

Alternatively, a rather exotic way of generating silyl enol ethers is via the Brook rearrangement of appropriate substrates.14

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.15161718 Silyl enol ethers are stable enough to be isolated, but are usually used immediately after synthesis.19

Generation of lithium enolate

Lithium enolates, one of the precursors to silyl enol ethers,2021 can also be generated from silyl enol ethers using methyllithium.2223 The reaction occurs via nucleophilic substitution at the silicon of the silyl enol ether, producing the lithium enolate and tetramethylsilane.2425

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).2627282930 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 SnCl4.31

Halogenation and oxidations

Halogenation of silyl enol ethers gives haloketones.3233

Acyloins form upon organic oxidation with an electrophilic source of oxygen such as an oxaziridine or mCPBA.34

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.3536 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.37

Hydrolysis

Hydrolysis of a silyl enol ether results in the formation of a carbonyl compound and a disiloxane.3839 In this reaction, water acts as an oxygen nucleophile and attacks the silicon of the silyl enol ether.40 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.41

Ring contraction

Cyclic silyl enol ethers undergo regiocontrolled one-carbon ring contractions.4243 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 acetals44 and have the general structure R3Si−O−C(OR)=CR2. These compounds are more nucleophilic than the silyl enol ethers of ketones (>C=O).45

References

  1. Peter Brownbridge (1983). "Silyl Enol Ethers in Synthesis - Part I". Synthesis. 1983: 1–28. doi:10.1055/s-1983-30204. /wiki/Doi_(identifier) ↩

  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. 978-0-470-51332-3 ↩

  3. 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). Silyl enol ethers. In Organic chemistry (Second ed., pp. 466-467). Oxford University Press. ↩

  5. Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers. In Organic chemistry (Second ed., pp. 466-467). Oxford University Press. ↩

  6. Clayden, J., Greeves, N., & Warren, S. (2012). Nucleophilic substitution at silicon. In Organic chemistry (Second ed., pp. 669-670). Oxford University Press. ↩

  7. 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 //doi.org/10.1021/ol900416x ↩

  8. 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 //doi.org/10.1016/B978-0-08-052349-1.00042-1 ↩

  9. 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 //doi.org/10.1016/B978-0-08-052349-1.00042-1 ↩

  10. Clayden, J., Greeves, N., & Warren, S. (2012). Kinetically controlled enolate formation. In Organic chemistry (Second ed., pp. 600-601). Oxford University Press. ↩

  11. 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 //doi.org/10.1016/B978-0-08-052349-1.00042-1 ↩

  12. Clayden, J., Greeves, N., & Warren, S. (2012). Thermodynamically controlled enolate formation. In Organic chemistry (Second ed., pp. 599-600). Oxford University Press. ↩

  13. 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. ↩

  14. 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. /wiki/Organic_Letters ↩

  15. Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers in aldol reactions. In Organic chemistry (Second ed., pp. 626-627). Oxford University Press. ↩

  16. 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. ↩

  17. 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. ↩

  18. 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 //doi.org/10.1016/B978-0-444-53349-4.00168-0 ↩

  19. Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers in aldol reactions. In Organic chemistry (Second ed., pp. 626-627). Oxford University Press. ↩

  20. 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 //doi.org/10.1016/B978-0-08-052349-1.00042-1 ↩

  21. Clayden, J., Greeves, N., & Warren, S. (2012). Kinetically controlled enolate formation. In Organic chemistry (Second ed., pp. 600-601). Oxford University Press. ↩

  22. 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 //doi.org/10.1021/jo00815a037 ↩

  23. Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers. In Organic chemistry (Second ed., pp. 466-467). Oxford University Press. ↩

  24. 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 //doi.org/10.1021/jo00815a037 ↩

  25. Clayden, J., Greeves, N., & Warren, S. (2012). Silyl enol ethers. In Organic chemistry (Second ed., pp. 466-467). Oxford University Press. ↩

  26. 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 //doi.org/10.1002/anie.201303192 ↩

  27. 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 //doi.org/10.1246/bcsj.49.779 ↩

  28. M. T. Reetz & A. Giannis (1981) Lewis Acid Mediated α-Thioalkylation of Ketones, Synthetic Communications, 11:4, 315-322, doi:10.1080/00397918108063611 //doi.org/10.1080/00397918108063611 ↩

  29. 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. ↩

  30. 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. ↩

  31. 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. ↩

  32. 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. 0-471-26422-9 ↩

  33. 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. ↩

  34. Organic Syntheses, Coll. Vol. 7, p.282 (1990); Vol. 64, p.118 (1986) Article. /wiki/Organic_Syntheses ↩

  35. 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 //doi.org/10.1039/P19960001935 ↩

  36. 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. ↩

  37. 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. ↩

  38. Clayden, J., Greeves, N., & Warren, S. (2012). Hydrolysis of enol ethers. In Organic chemistry (Second ed., pp. 468-469). Oxford University Press. ↩

  39. 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 //doi.org/10.1016/S0032-3861(01)00602-4 ↩

  40. Clayden, J., Greeves, N., & Warren, S. (2012). Hydrolysis of enol ethers. In Organic chemistry (Second ed., pp. 468-469). Oxford University Press. ↩

  41. Clayden, J., Greeves, N., & Warren, S. (2012). Hydrolysis of enol ethers. In Organic chemistry (Second ed., pp. 468-469). Oxford University Press. ↩

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  44. 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. ↩

  45. 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. ↩