[2344-80-1]  · C4H11ClSi  · (Chloromethyl)trimethylsilane  · (MW 122.67)

(reagent for direct alkene synthesis;2 electrophile for the formation of a variety of functionalized synthetic intermediates for alkene synthesis;3 alkylation adducts are frequently a source of fluoride-induced reactive intermediates;4 readily undergoes metal-halogen exchange to generate a reagent for Peterson methylenation5)

Alternate Name: trimethylsilylmethyl chloride.

Physical Data: bp 97-98 °C; d 0.886 g cm-3.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: highly flammable liquid; corrosive; irritant; use in a fume hood.

Reactions with Carbonyl Compounds.

Terminal alkenes are efficiently generated upon treatment of an aldehyde or ketone with Me3SiCH2Cl in the presence of Triphenylphosphine in a sealed tube (eq 1).2 Reaction times are generally not more than 60 min, and the method is operationally simple, although use of this protocol for methylenation is limited to substrates which lack enolizable a-hydrogens, since in such cases studied, silyl enol ether formation is a competitive pathway.

Conversion of aldehydes and ketones to a,b-epoxy trimethylsilanes is readily achieved by treatment of Me3SiCH2Cl with the appropriate alkyllithium reagent at low temperature, and subsequent quenching with the desired carbonyl compound.6 It is critical that s-Butyllithium be used as the lithiating reagent, as use of n-Butyllithium results in attack at silicon and use of t-Butyllithium results in metal-halogen exchange. The resultant a,b-epoxy trimethylsilanes undergo facile hydrolysis under relatively mild conditions to provide the corresponding aldehydes in good yields (eq 2). A variety of substrates have been successfully subjected to this sequence, including a,b-unsaturated carbonyl compounds and sterically congested aldehydes and ketones.

In the presence of Cesium Fluoride in DMF, Me3SiCH2Cl reacts with benzaldehyde to form phenyloxirane in 60% yield (eq 3);7 this method has not yet proven to be a generally applicable route to epoxides.

Electrophile for O-, N-, and S-Alkylations.

A novel method for phenol homologation utilizes Me3SiCH2Cl to trap phenoxides, forming trimethylsilylmethyl phenyl ethers which, upon treatment with s-butyllithium, undergo 1,2-Wittig rearrangement of the intermediate lithiated trimethylsilylmethyl species to produce trimethylsilyl-substituted benzyl alcohols in good yields. Subjecting these phenylsilylmethanols to basic hydrolysis with methanolic potassium hydroxide produces the homologated phenols (eq 4).8

Much of the utility of Me3SiCH2Cl is derived from the lability of the methylene carbon-silicon bond in its alkylation products from nitrogen-containing nucleophiles. The subsequent, relatively mild conditions of fluoride treatment effect 1,3-dipole formation. This fluoride-promoted azomethine ylide generation methodology constitutes a highly stereoselective means for the synthesis of pyrroles by the trapping of the reactive intermediate with Dimethyl Fumarate or Dimethyl Maleate (eq 5).4

Other dipolarophiles, including aldehydes, nitroalkenes, styrenes, and functionalized alkynes (eq 6), have also proven to be effective cycloaddition substrates for ylides generated in this fashion.9

Intramolecular trapping of ylides derived from the Me3SiCH2Cl alkylation adducts of a variety of 3- and 4-substituted benzylamines proceeds through a Sommelet-Hauser pathway, providing the rearranged products in good yields (eq 7).10

Azolylmethyl anions, generated by the fluoride-induced desilylation of Me3SiCH2Cl adducts of pyrroles, imidazoles, pyrazoles, triazoles, and tetrazoles, and azinonylmethyl anions similarly derived from (trimethylsilylmethyl)azinones, have demonstrated efficacy in the addition reactions to carbonyl compounds.11

Sulfur alkylation products of Me3SiCH2Cl have also been used as a convenient source of reactive intermediates. Lithiated (2-benzothiazolylthio)(trimethylsilyl)methane (eq 8) functions as a synthetic equivalent for the mercaptomethyl anion by (a) reaction with an electrophile, (b) fluoride-promoted desilylation/reaction with a carbonyl compound, and (c) alkyllithium addition to the benzothiazole 2-position.12

Thiiranes have been prepared by the reaction of aldehydes with S-methyl S-trimethylsilylmethyl N-(p-tolylsulfonyl)dithioiminocarbonate in the presence of cesium fluoride (eq 9).13 This novel route to thiiranes utilizes the 1,3-dipolar cycloaddition of the iminothiocarbonyl ylide derived from a Me3SiCH2Cl alkylated thiol to aldehydes.

Preparation of Other Reagents.

One of the principal uses of this reagent has been for the formation of Trimethylsilylmethylmagnesium Chloride, most often used for the methylenation of carbonyl compounds;5 however, since both this reagent and the corresponding lithio reagent are now widely available commercially, its use in this capacity has diminished considerably. Similarly, chloromethyltrimethylsilane has been used to prepare many other now commercially available reagents, including trimethylsilylmethyl acetate, trimethylsilylmethyl isocyanide, Trimethylsilyldiazomethane and trimethylsilylmethyl trifluoromethanesulfonate, each useful for a variety of synthetic transformations.

Related Reagents.

(Iodomethyl)trimethylsilane; Trimethylsilylmethyllithium; Trimethylsilylmethylmagnesium Chloride; Trimethylsilylmethylpotassium; Trimethylsilylmethyl Trifluoromethanesulfonate.

1. Anderson, R. S 1985, 717.
2. Sekiguchi, A.; Ando, W. JOC 1979, 44, 413.
3. (a) Djahanbini, D.; Cazes, B.; Gore, J.; Gobert, F. T 1985, 41, 867. (b) Kawashima, T.; Ishii, T.; Inamoto, N. BCJ 1987, 60, 1831.
4. Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. JOC 1985, 50, 4006.
5. (a) Ager, D. J. S 1984, 384. (b) Chan, T. H.; Chang, E. JOC 1974, 39, 3264. (c) Peterson, D. J. JOC 1968, 33, 780.
6. Burford, C.; Cooke, F.; Roy, G.; Magnus, P. T 1983, 39, 867.
7. (a) Kessar, S. V.; Singh, P.; Kaur, N. P.; Chawla, U.; Shukla, K.; Aggarwal, P.; Venugopal, D. JOC 1991, 56, 3908. (b) Kessar, S. V.; Singh, P.; Venugopal, D. IJC(B) 1987, 26B, 605.
8. Eisch, J. J.; Galle, J. E.; Piotrowski, A.; Tsai, M.-R. JOC 1982, 47, 5051.
9. (a) Padwa, A.; Chen, Y. Y.; Chiacchio, U.; Dent, W. T 1985, 41, 3529. (b) Padwa, A.; Dent, W. OS 1988, 67, 133. See also (c) Pandey, G.; Lakshmaiah, G.; Kumaraswamy, G. CC 1992, 1313. (d) Anderson, W. K.; Kinder, F. R. JHC 1990, 27, 975.
10. Shirai, N.; Watanabe, Y.; Sato, Y. JOC 1990, 55, 2767.
11. (a) Shimizu, S.; Ogata, M. JOC 1988, 53, 5160. (b) Shimizu, S.; Ogata, M. JOC 1986, 51, 3897.
12. (a) Katritzky, A. R.; Kuzmierkiewicz, W.; Aurrecoechea, J. M. JOC 1987, 52, 844. See also (b) Terao, Y.; Aono, M.; Imai, N.; Achiwa, K. CPB 1987, 35, 1734.
13. (a) Tominaga, Y.; Ueda, H.; Ogata, K.; Kohra, S.; Hojo, M.; Ohkuma, M.; Tomita, K.; Hosomi, A. TL 1992, 33, 85. (b) Tominaga, Y.; Matsuoka, Y.; Kamio, C.; Hosomi, A. CPB 1989, 37, 3168.

Lawrence G. Hamann & Todd K. Jones

Ligand Pharmaceuticals, San Diego, CA, USA

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