Trimethylsilyllithium

Me3SiLi

[18000-27-6]  · C3H9LiSi  · Trimethylsilyllithium  · (MW 80.15)

(synthesis of b-silyl ketones;1 homologation of sterically hindered ketones;2 inversion of alkene stereochemistry3)

Preparative Method: by the reaction of Hexamethyldisilane and Methyllithium in HMPA.

Handling, Storage, and Precautions: should be used immediately after preparation. The red HMPA solution of trimethylsilyllithium is sensitive to air and moisture. HMPA is carcinogenic and should be used only in a well-ventilated hood. Contact with eyes and skin should be avoided.

General Discussion.

Triorganosilyl alkali metal species in which at least one substituent on silicon is an aryl group were prepared by cleavage of the corresponding hexaorganodisilanes by alkali metals in the 1950s; however, the hexaalkyldisilanes are inert to metal cleavage.4 The generation of trimethylsilyl alkali metal species has more recently been accomplished by the reaction of hexamethyldisilane and potassium methoxide,3 sodium methoxide,5 or methyllithium1 in HMPA. Trimethylsilylpotassium (TMSK) and trimethylsilylsodium have also been obtained by the reaction of hexamethyldisilane and KH or NaH in HMPA.6 The most useful method for the generation of trimethylsilyllithium (TMSLi) is the procedure reported by Still.1 A deep red solution of TMSLi is obtained upon reaction of hexamethyldisilane with methyllithium in HMPA at 0 °C in 15 min (eq 1); however, further reaction leading to a disilane anion is possible (eq 2).7 The solid state structure of TMSLi has been determined by single crystal X-ray analysis as a hexameric species.8

TMSLi adds to cyclohexenone in THF-HMPA to give exclusively the 1,4-addition product (eq 3).1 The intermediate enolate may be stereoselectively alkylated at carbon with alkyl halides, or O-silylated with Chlorotrimethylsilane to provide the enol ether. Nucleophilic 1,4-addition to cyclohexenones is quite stereoselective. Reaction of 5-methylcyclohex-2-enone with TMSLi occurs predominantly by axial attack, resulting in a 92:8 ratio of axial to equatorial products.9 TMSLi also undergoes diastereoselective nucleophilic addition to 1-naphthyloxazolines (eq 4);10 however, the addition of the silyl nucleophile is not as selective as the addition of simple alkyllithium reagents. The diminished diastereoselection is presumably due to the presence of HMPA required in the generation of TMSLi.

The b-silyl ketones obtained by 1,4-addition of TMSLi have been employed in the synthesis of alkenic acids by means of a silicon directed Baeyer-Villager oxidation (eq 5).11 Peracid oxidation of the b-silyl ketone results in formation of the unstable seven-membered ring lactone which undergoes acid-catalyzed ring opening with concomitant stereoselective 1,2-migration of the trimethylsilyl group to provide the stable six-membered ring lactone. Saponification followed by stereoselective alkene generation, either via anti-elimination using Boron Trifluoride Etherate or syn-elimination using Potassium Hydride, leads to the trans- or cis-alkene, respectively. The directed Baeyer-Villager approach has been applied to the stereoselective synthesis of exo- and endo-brevicomin.12 The regioselectivity of the b-silyl-directed oxidation is not completely controlled. Quaternary carbons migrate preferentially over a less substituted b-silyl alkyl group.

TMSLi also undergoes direct nucleophilic 1,2-addition to saturated ketones and aldehydes. A novel route for the homologation of sterically hindered ketones which involves the addition of TMSLi to the a-trimethylsilyloxy aldehyde derived from the cyanohydrin of a ketone has been developed.2 The initial alkoxide undergoes an intramolecular oxygen-to-oxygen silyl migration, leading to a b-hydroxy silane (eq 6). Treatment of the b-hydroxy silane with excess base induces alkene formation by a Peterson alkenation reaction. Hydrolysis of the silyl enol ether product then provides the homologated aldehyde. Reduction of the aldehyde to the hydroxymethyl group provides a key intermediate in the synthesis of aphidicolin (eq 6),2 stemodin, and stemodinone.13

Stereoselective nucleophilic addition of TMSLi to 2-methylcyclohexanone provides an intermediate for the study of the stereochemistry of the aliphatic Brook rearrangement (eq 7).14 The reverse Brook rearrangement has provided a method for the synthesis of a variety of (a-hydroxyalkyl)trialkylsilanes which does not require the difficult preparation of trialkylsilyl anions.15 The method involves nucleophilic addition of readily available Tri-n-butylstannyllithium to a carbonyl, O-silylation, and subsequent O-to-C migration of the silyl group induced by Sn-Li transmetalation (eq 8). The yields of (a-hydroxyalkyl)trimethylsilanes obtained by this procedure are frequently greater than the yields obtained by the direct addition of TMSLi. Direct addition of TMSLi16 or TMSK3 to epoxides has also been reported. Due to the stereospecific nature of the Peterson alkenation reaction, the epoxidation and TMSK deoxygenation of an alkene can result in stereospecific inversion of the double bond stereochemistry (eq 9). The epoxidation-deoxygenation sequence has been employed as a method to protect an alkene during catalytic hydrogenation.16 Allylsilanes may be prepared by the SN2 displacement of allyl chlorides.17 The reaction appears to be a direct nucleophilic displacement and does not involve electron transfer processes. TMSLi can also undergo transmetalation to a variety of other organometallic species such as Trimethylsilylcopper. Vinylsilanes can be obtained by the reaction of an alkyne with TMSLi in the presence of MnII and methylmagnesium chloride.18 TMSLi has not been used as extensively as the more readily accessible dimethylphenylsilyllithium for generation of other silyl organometallic reagents.4,19

Related Reagents.

Dimethyl(phenyl)silane; Hexamethyldisilane; Trimethylsilylpotassium.


1. Still, W. C. JOC 1976, 41, 3063.
2. Corey, E. J.; Tius, M. A.; Das, J. JACS 1980, 102, 1742.
3. Dervan, P. B.; Shippey, M. A. JACS 1976, 98, 1265.
4. Gilman, H.; Lichtenwalter, G. D. JACS 1958, 80, 608.
5. Sakurai, H.; Okada, A.; Kira, M.; Yonezawa, K. TL 1971, 1511.
6. Corriu, R. J. P.; Guerin, C. CC 1980, 168.
7. Hudrlik, P. F.; Waugh, M. A.; Hudrlik, A. M. JOM 1984, 271, 69.
8. Ilsley, W. H.; Schaaf, T. F.; Glick, M. D.; Oliver, J. P. JACS 1980, 102, 3769.
9. Wickham, G.; Olszowy, H. A.; Kitching, W. JOC 1982, 47, 3788.
10. Barner, B. A.; Meyers, A. I. JACS 1984, 106, 1865.
11. Hudrlik, P. F.; Hudrlik, A. M.; Nagendrappa, G.; Yimenu, T.; Zellers, E. T.; Chin, E. JACS 1980, 102, 6894.
12. Hudrlik, P. F.; Hudrlik, A. M.; Yimenu, T.; Waugh, M. A.; Nagendrappa, G. T 1988, 44, 3791.
13. Corey, E. J.; Tius, M. A.; Das, J. JACS 1980, 102, 7612.
14. Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. JACS 1982, 104, 6809.
15. Linderman, R. J.; Ghannam, A. JACS 1990, 112, 2392.
16. Oliver, J. E.; Schwarz, M.; Klun, J. A.; Lusby, W. R.; Waters, R. A. TL 1993, 34, 1593.
17. Smith, J. G.; Drozda, S. E.; Petraglia, S. P.; Quinn, N. R.; Rice, E. M.; Taylor, B. S.; Viswanathan, M. JOC 1984, 49, 4112.
18. Hibino, J.; Nakatsukasa, S.; Fugami, K.; Matsubara, S.; Oshima, K.; Nozaki, H. JACS 1985, 107, 6416.
19. Fleming, I.; Newton, T. W.; Roessler, F. JCS(P1) 1981, 2527.

Russell J. Linderman

North Carolina State University, Raleigh, NC, USA



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