[2857-97-8]  · C3H9BrSi  · Bromotrimethylsilane  · (MW 153.09)

(mild and selective reagent for cleavage of lactones, epoxides, acetals, phosphonate esters and certain ethers; effective reagent for formation of silyl enol ethers; can function as brominating agent)

Alternate Name: TMS-Br.

Physical Data: bp 79 °C; d 1.188 g cm-3; n20D 1.4240; fp 32 °C.

Solubility: sol CCl4, CHCl3, CH2Cl2, ClCH2CH2Cl, MeCN, toluene, hexanes; reactive with THF (ethers), alcohols, and somewhat reactive with EtOAc (esters).

Form Supplied in: colorless liquid, packaged in ampules.

Analysis of Reagent Purity: well characterized by 1H, 13C, and 29Si NMR spectroscopy.

Preparative Methods: although many methods are reported,1 only a few are provided here: Chlorotrimethylsilane undergoes halogen exchange with either Magnesium Bromide2 in Et2O or Sodium Bromide3 in MeCN, which allows in situ reagent formation (eq 1); alternatively, Hexamethyldisilane reacts with Bromine in benzene solution or neat, to afford only TMS-Br with no byproducts (eq 2).4 TMS-Br may also be generated by reaction of hexamethyldisiloxane and Aluminum Bromide (eq 3).5 However, it should be noted that the reactivity of in situ generated reagent appears to depend upon the method of preparation.

Purification: by distillation.

Handling, Storage, and Precautions: extremely sensitive to light, air, and moisture; fumes in air due to hydrolysis (HBr), and becomes discolored upon prolonged storage (free Br2).

Ester Cleavage.6

Although esters are readily cleaved with Iodotrimethylsilane, reaction of esters with TMS-Br under similar conditions gives somewhat lower yields of silyl esters or acids upon hydrolysis (eq 4). Lactones, however, react with TMS-Br at 100 °C to afford o-bromocarboxylic acids after hydrolysis of the silyl ester (eq 5).7

Ether Cleavage.

THF8 reacts with TMS-Br, thereby rendering ethereal solvents incompatible with the reagent. Smooth removal of the methoxymethyl (MOM) protecting group can be accomplished with TMS-Br at 0 °C (eq 6).9 Whereas acetals, THP and silyl ethers are slowly cleaved with TMS-Br, the reagent generated in situ effects selective MOM ether cleavage in the presence of an acetonide.10 The majority of published ether cleavages have been accomplished with TMS-I, although limited data show that the more vigorous conditions necessary for ethyl ether cleavage also result in bromide formation.8

Cleavage of Epoxides.

Epoxide opening with TMS-Br occurs to provide the primary alkyl bromide at -60 °C (eq 7).8

Cleavage of Acetals.

Acetals can be cleaved by analogy to ethers, providing the parent carbonyl species.3c,6b Glycosyl bromides have been prepared from the corresponding acetate by reaction with TMS-Br in CHCl3 at rt (eq 8).11 In conjunction with CoBr2 and Tetra-n-butylammonium Bromide, TMS-Br converts the glucopyranose to the a-D-glucoside in the presence of an alcohol (eq 9).12

An interesting solvent effect was noted in the cleavage of the acetonide moiety in some nucleoside derivatives (eq 10).13 In CH2Cl2, TMS-Br converted the acetonide to the anhydrouridine within 1.5 h, but in MeCN the bromide is formed after 10 min.

Formation of Enol Ethers.14

Bromotrimethylsilane with Triethylamine in DMF is an effective medium for production of thermodynamic (Z) silyl enol ethers (eq 11).

Formation of Alkyl Bromides.6b

Alcohols react with excess TMS-Br (1.5-4 equiv) at 25-50 °C to form the alkyl bromide and hexamethyldisiloxane (eq 12). Benzylic and tertiary alcohols react faster than secondary alcohols.

Reaction with Acid Chlorides.15

Acid bromides may be prepared from acid chlorides by reaction with TMS-Br (eq 13).

Cleavage of Phosphonate Esters.16

Compared to the reactivity of TMS-I with phosphonate and phosphate esters, TMS-Br is more selective and will cleave phosphonate esters even in the presence of carboxylic esters and carbamates. Benzyl ester protecting groups on aryl phosphates are selectively removed with TMS-Br.17 The reaction of phosphonate esters with TMS-Br proceeds through a mechanism similar to ester cleavage, providing a silyl ester which is subsequently hydrolyzed with MeOH or H2O (eq 14).

Reaction with Amines.

Amines react with TMS-Br to form isolable adducts, which react readily with ketones to form enamines under mild conditions (eq 15).18

Conjugate Addition.

a,b-Unsaturated ketones undergo conjugate addition with TMS-Br. Treatment of the intermediate with p-Toluenesulfonic Acid and ethylene glycol provides b-bromoethyldioxolanes (eq 16).19


o-Unsaturated carboxylic acids react with TMS-Br in the presence of a tertiary amine in DMSO yielding bromolactones, resulting from cis addition across the double bond (eq 17).20

Ylide Formation.

Methylenetriphenylphosphorane reacts with TMS-Br to provide the corresponding ylide (eq 18).21

1. Schmidt, A. H. Aldrichim. Acta 1981, 14 (2), 31.
2. Krüerke, U. CB 1962, 95, 174.
3. (a) Scheibye, S.; Thomsen, I.; Lawesson, S. O. BSB 1979, 88, 1043. (b) Olah, G. A.; Gupta, B. G. B.; Malhotra, R.; Narang, S. C. JOC 1980, 45, 1638. (c) Schmidt, A. H.; Russ, M. CB 1981, 114, 1099.
4. Sakurai, H.; Sasaki, K.; Hosomi, A. TL 1980, 21, 2329.
5. (a) Voronkov, M. G.; Dolgov, B. N.; Dmitrieva, N. A. DOK 1952, 84, 959. (b) Gross, H.; Böck, C.; Costisella, B.; Gloede, J. JPR 1978, 320, 344.
6. (a) Ho, T. L.; Olah, G. A. S 1977, 417. (b) Jung, M. E.; Hatfield, G. L. TL 1978, 4483.
7. Kricheldorf, H. R. AG(E) 1979, 18, 689.
8. Kricheldorf, H. R.; Mörber, G.; Regel, W. S 1981, 383.
9. Hanessian, S.; Delorme, D.; Dufresne, Y. TL 1984, 25, 2515.
10. Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward, D. E.; Au-Yeung, B.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C. H.; Chênevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.; Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.; Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan Babu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong, H. N.-C. JACS 1981, 103, 3213.
11. Gillard, J. W.; Israel, M. TL 1981, 22, 513.
12. Morishima, N.; Koto, S.; Kusuhara, C.; Zen, S. CL 1981, 427.
13. Logue, M. W. Carbohydr. Res. 1975, 40, C9.
14. Ahmad, S.; Khan, M. A.; Iqbal, J. SC 1988, 18, 1679.
15. Schmidt, A. H.; Russ, M.; Grosse, D. S 1981, 216.
16. (a) McKenna, C. E.; Schmidhauser, J. CC 1979, 739. (b) Breuer, E.; Safadi, M.; Chorev, M.; Gibson, D. JOC 1990, 55, 6147.
17. Lazar, S.; Guillaumet, G. SC 1992, 22, 923.
18. Comi, R.; Franck, R. W.; Reitano, M.; Weinreb, S. M. TL 1973, 3107.
19. Hsung, R. P. SC 1990, 20, 1175.
20. Iwata, C.; Tanaka, A.; Mizuno, H.; Miyashita, K. H 1990, 31, 987.
21. Seyferth, D.; Grim, S. O. JACS 1961, 83, 1610.

Michael J. Martinelli

Lilly Research Laboratories, Indianapolis, IN, USA

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