Ethyl Lithio(trimethylsilyl)acetate1

[-]  · C7H15LiO2Si  · Ethyl Lithio(trimethylsilyl)acetate  · (MW 166.25)

(reacts with carbonyl compounds to give a,b-unsaturated esters2)

Solubility: sol ethereal solvents; reacts with protic solvents.

Preparative Methods: available by reaction of ethyl trimethylsilylacetate with Lithium Diisopropylamide, lithium isopropylcyclohexylamide, or lithium dicyclohexylamide in THF at low temperature.1b,2

Handling, Storage, and Precautions: as with any other organometallic agent, the reagent should be used under an inert atmosphere.

Peterson Alkenation.

The use of a Peterson approach for the preparation of a,b-unsaturated esters can hold a number of advantages over a Wittig reaction or one of its derivatives.2 In addition to an easily removed byproduct, hexamethyldisiloxane, silyl esters can provide the desired a,b-unsaturated esters in moderate to good yields when a Wittig approach fails.1a,3 Stereoselection can also be observed. In some cases, this can be increased by use of a magnesium enolate and acidic workup.1a,4 While the analogous Wittig approach requires the use of a stabilized ylide and, hence, usually results in the formation of just the (E) isomer (or the thermodynamically more stable isomer) of the a,b-unsaturated ester product, the Peterson reaction can either provide a mixture of the isomeric product alkenes, or the (Z) isomer if selection is seen.5 The stereochemical differences can be interpreted in terms of the Wittig reaction being under thermodynamic control, while the Peterson method is kinetically controlled. Thus stereochemical control during the addition of the silicon reagent can result in stereoselective formation of the a,b-unsaturated ester (eq 1).6


Alkylation of the title enolate (1) with alkyl iodides in the presence of HMPA allows for the preparation of higher a-silyl esters.7

Ester enolate (1) can be alkylated by vinyl halides in the presence of a nickel catalyst to afford a-trimethylsilyl-b,g-unsaturated esters. These products react with a wide variety of electrophiles in the presence of a Lewis acid to provide g-subsituted a,b-unsaturated esters (eq 2).8

Other Electrophiles.

In addition to carbonyl compounds, ester enolate (1) also reacts with other electrophiles. With nitrones, the product is dependent upon the structure of the nitrone: a,N-dialkyl nitrones provide alkenes, while a-aryl-N-alkyl nitrones or a,N-diaryl nitrones usually give aziridines.9 With the phenylhydrazone of a 1,2-dicarbonyl compound, reaction with (1) provides a convenient preparation of 3(2H)-pyridazinones (eq 3).10


The ester enolates derived from methyl or t-butyl trimethylsilylacetate react in an analogous manner to ethyl ester (1) with carbonyl compounds.1a,3,11 However, with the t-butyl ester the carbonyl reactant has to be an aldehyde as steric problems result in enolization of ketonic substrates.12 As with the ethyl ester, addition of the enolate to the carbonyl substrate may allow for stereochemical control of the resultant a,b-unsaturated ester geometry.5c,13 In addition, the groups attached to silicon can be modified without substantial changes to the reactivity with carbonyl compounds.14

It is also possible to introduce additional functionality into the a-silyl ester. Thus t-butyl (trimethylsilyl)chloroacetate reacts with carbonyl compounds after ester enolate formation with LDA to form t-butyl a-chloro-a,b-unsaturated esters, although the elimination of the silyl moiety may have to be encouraged by the use of Thionyl Chloride,3,15 as it also is with the a-bromo analog.16 A second silyl group, with its additional bulk, can allow for high stereoselection, although the outcome does depend on the metal counterion used in the enolate.12,17

Analogs of the ester enolate derived from higher carboxylic acids can also be prepared by the addition of an organometallic agent to Methyl 2-Trimethylsilylacrylate (2). The resultant ester enolate from the Michael addition can be used for a subsequent Peterson alkenation reaction when reacted with a carbonyl compound (eq 4).18

The sterically demanding t-butyl ester enolate reacts with acylimidazoles to provide b-keto esters (eq 5).19

The ester enolates derived from the methyl or t-butyl esters react with lactones to yield vinyl ethers as a mixture of isomers (eq 6).20

With cyclopentenone derivatives, 1,4-addition is observed for the ester enolates of methyl and t-butyl trimethylsilylacetate,21 although 1,2-addition occurs with acyclic conjugated enals.11,12 With a steroidal cyclopentenone substrate, both 1,2- and 1,4-addition were observed.22 Conjugate addition is observed for the methyl ester with chiral vinyl sulfoxides. High enantioselectivity can be attained (eq 7).23

As with the ethyl ester, other ester derivatives can be alkylated through their lithium enolates.24 Use of the menthyl ester provides a route to chiral silanes (eq 8).25

Related Reagents.

t-Butyl a-Lithiobis(trimethylsilyl)acetate; t-Butyl Trimethylsilylacetate; Ethyl Bromozincacetate; Ethyl Lithioacetate; Ethyl Trimethylsilylacetate; Ketene Bis(trimethylsilyl) Acetal; Ketene t-Butyldimethylsilyl Methyl Acetal; 1-Methoxy-2-trimethylsilyl-1-(trimethylsilyloxy)ethylene; Methyl (Methyldiphenylsilyl)acetate; Methyl 2-Trimethylsilylacrylate; Triethyl Phosphonoacetate; Trimethylsilylacetic Acid.

1. (a) Ager, D. J. OR 1990, 38, 1. (b) Ager, D. J. S 1984, 384; (c) Fleming, I. In Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 3, p 541. (d) Birkofer, L.; Stuhl, O. Top. Curr. Chem. 1980, 88, 33.
2. Shimoji, K.; Taguchi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 1620.
3. Crimmin, M. J.; O'Hanlon, P. J.; Rogers, N. H. JCS(P1) 1985, 541.
4. Larchevêque, M.; Debal, A. CC 1981, 877.
5. (a) &CCcaron;erný, I.; Pouzar, V.; Drašar, P.; Tureček, F.; Havel, M. CCC 1986, 51, 128. (b) Novák, L.; Rohály, J.; Poppe, L.; Hornyánszky, G.; Kolonits, P.; Zelei, I.; Fehér, I.; Fekete, J.; Szabó, E.; Záhorszky, U.; Jávor, A.; Szántay, C. LA 1992, 145. (c) Larson, G. L.; Prieto, J. A.; Hernández, A. TL 1981, 22, 1575. (d) Strekowski, L.; Visnick, M.; Battiste, M. A. TL 1984, 25, 5603. (e) Szychowski, J.; MacLean, D. B. CJC 1979, 57, 1631.
6. Pak, H.; Dickson, J. K.; Fraser-Reid, B. JOC 1989, 54, 5357. Drian, C. L.; Greene, A. E. JACS 1982, 104, 5473. Greene, A. E.; Drian, C. L.; Crabbé, P. JOC 1980, 45, 2713.
7. Cunico, R. F. JOC 1990, 55, 4474.
8. Albaugh-Robertson, P.; Katzenellenbogen, J. A. JOC 1983, 48, 5288.
9. Tsuge, O.; Sone, K.; Urano, S.; Matsuda, K. JOC 1982, 47, 5171.
10. Patel, H. V.; Vyas, K. A.; Pandey, S. P.; Tavares, F.; Fernandes, P. S. SC 1991, 21, 1935.
11. Tulshian, D. B.; Fraser-Reid, B. JACS 1981, 103, 474.
12. Hartzell, S. L.; Rathke, M. W. TL 1976, 2737.
13. Larcheveque, M.; Legueut, C.; Debal, A.; Lallemand, J. Y. TL 1981, 21, 1595.
14. Larson, G. L.; Quiroz, F.; Suárez, J. SC 1983, 13, 833.
15. Chan, T. H.; Moreland, M. TL 1978, 515.
16. Zapata, A.; Ferrer G., F. SC 1986, 16, 1611.
17. Boeckman, R. K.; Chinn, R. L. TL 1985, 26, 5005.
18. Tsuge, O.; Kanemasa, S.; Ninomiya, Y. CL 1984, 1993.
19. Hartzell, S. L.; Rathke, M. W. TL 1976, 2757.
20. Sauvé, G.; Deslongchamps, P. SC 1985, 15, 201; Takahashi, A.; Kirio, Y.; Sodeoka, M.; Sasai, H.; Shibasaki, M. JACS 1989, 111, 643.
21. Nishiyama, H.; Sakuta, K.; Itoh, K. TL 1984, 25, 2487. Oppolzer, W.; Guo, M.; Baettig, K. HCA 1983, 66, 2140.
22. Wicha, J.; Kabat, M. M. JCS(P1) 1985, 1601.
23. Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.; Cun-Heng, H.; Clardy, J. T 1986, 42, 2919.
24. Hudrlik, P. F.; Peterson, D.; Chou, D. SC 1975, 5, 359; Paquette, L. A.; Maynard, G. D.; Ra, C. S.; Hoppe, M. JOC 1989, 54, 1408.
25. Paquette, L. A.; Gilday, J. P.; Ra, C. S.; Hoppe, M. JOC 1988, 53, 704. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. JOC 1989, 54, 1399.

David J. Ager

The NutraSweet Company, Mount Prospect, IL, USA

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