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

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 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

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

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.

References

  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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