[2916-68-9]  · C5H14OSi  · 2-(Trimethylsilyl)ethanol  · (MW 118.28)

(protecting reagent for carboxyl, phosphoryl, hydroxyl, and amino groups)

Physical Data: bp 50-52 °C/10 mmHg, 71-73 °C/35 mmHg; d 0.825 g cm-3.

Form Supplied in: colorless liquid; 99% purity; widely available.

Preparative Methods: three methods of preparation have been reported: (a) from the treatment of ethyl bromoacetate with Zinc followed by the reaction with Chlorotrimethylsilane1 and subsequent reduction of the resultant Ethyl Trimethylsilylacetate with Lithium Aluminum Hydride2,3 or Borane-Tetrahydrofuran4 (eq 1); (b) from the hydroboration/oxidation5,6 or oxymercuration/demercuration7 of Vinyltrimethylsilane (eq 2); and (c) most conveniently, by the reaction of the Grignard reagent formed from (Chloromethyl)trimethylsilane with Paraformaldehyde (eq 3).8

Handling, Storage, and Precautions: corrosive; irritant.

A variety of methods are available for the protection of carboxylic acids as 2-(trimethylsilyl)ethyl esters.9 2-(Trimethylsilyl)ethyl esters are stable to conditions used in peptide synthesis. Deprotection of the ester is readily accomplished by treatment with Tetra-n-butylammonium Fluoride (TBAF).9 Hemisuccinates have been prepared indirectly under nonacidic conditions by monoprotection of succinic anhydride as 2-(trimethylsilyl)ethyl esters followed by esterification (eq 4) and then selective deprotection of the resultant diester (eq 5).10

Transesterification of methyl esters to 2-(trimethylsilyl)ethyl esters under mild and neutral conditions takes place in the presence of Titanium Tetraisopropoxide (eqs 6-8).11 Deprotection of the 2-(trimethylsilyl)ethyl ester in the presence of an O-TBDMS protected secondary hydroxyl group has been achieved (eq 9).11b An alternative method for the transesterification uses 1,8-Diazabicyclo[5.4.0]undec-7-ene/Lithium Bromide and 2-(trimethylsilyl)ethanol.12

Protection of hydroxyl groups as 2-(trimethylsilyl)ethyl ethers13a and 2-(trimethylsilyl)ethyl carbonates13b (eq 10) has been utilized as illustrated below. The 2-(trimethylsilyl)ethyl carbonate group can be cleaved under mild conditions using TBAF in dry THF (eq 11).13b

Methods for the protection of pyranosides and furanosides as 2-(trimethylsilyl)ethyl glycosides (eq 12) and deprotection using dry Lithium Tetrafluoroborate in MeCN have been developed (eq 13).14

2-(Trimethylsilyl)ethanol has been used as a protecting group in phosphate monoester synthesis and involves the use of 2-(trimethylsilyl)ethyl dichlorophosphite (eq 14).15 Bis[2-(trimethylsilyl)ethyl] N,N-diisopropylphosphoramidite has been prepared from dichloro(diisopropylamino)phosphine and 2-(trimethylsilyl)ethanol and used as a phosphitylating agent in the synthesis of phosphotyrosine containing peptides (eq 15).16

2-(Trimethylsilyl)ethoxycarbonyl (Teoc) groups have been used to protect amine functionalities (eq 16).17 Using a mixture of tetra-n-butylammonium chloride and KF.2H2O deprotects the Teoc group.18 N-Debenzylation and concurrent protection as N-Teoc results when tertiary N-benzylamines are treated with 2-(Trimethylsilyl)ethyl Chloroformate.19

A new method for the synthesis of imidazolones involves the replacement of the C-2 nitro group of N-protected dinitroimidazoles by nucleophilic addition of the sodium salt of 2-(trimethylsilyl)ethanol (eq 17).20

Reaction of 2-(trimethylsilyl)ethyl benzenesulfenate with halides in the presence of TBAF yields phenyl sulfoxides (eq 18).21 2-(Trimethylsilyl)ethyl benzenesulfenate is prepared by the reaction of Benzenesulfenyl Chloride and the lithium salt of 2-(trimethylsilyl)ethanol.

1. Fessenden, R. J.; Fessenden, J. S. JOC 1967, 32, 3535.
2. Gerlach, H. HCA 1977, 60, 3039.
3. Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.; Dahmen, J.; Noori, G.; Stenvall, K. JOC 1988, 53, 5629.
4. Rosowsky, A.; Wright, J. E. JOC 1983, 48, 1539.
5. Soderquist, J. A.; Hassner, A. JOM 1978, 156, C12.
6. Soderquist, J. A.; Brown, H. C. JOC 1980, 45, 3571.
7. Soderquist, J. A.; Thompson, K. L. JOM 1978, 159, 237.
8. Mancini, M. L.; Honek, J. F. TL 1982, 23, 3249.
9. From acids: (a) Sieber, P. HCA 1977, 60, 2711. (b) Brook, M. A.; Chan, T. H. S 1983, 201. (c) White, J. D.; Jayasinghe, L. R. TL 1988, 29, 2139. From an acid chloride: see Ref. 2. From an anhydride: Vedejs, E.; Larsen, S. D. JACS 1984, 106, 3030. For cleavage: see Ref. 9a, and Forsch, R. A.; Rosowsky, A. JOC 1984, 49, 1305.
10. Pouzar, V.; Drasar, P.; Cerny, I.; Havel, M. SC 1984, 14, 501.
11. (a) Seebach, D.; Hungerbühler, E.; Naef, R.; Schnurrenberger, P.; Weidmann, B.; Züger, M. S 1982, 138. (b) Férézou, J. P.; Julia, M.; Liu, L. W.; Pancrazi, A. SL 1991, 618.
12. Seebach, D.; Thaler, A.; Blaser, D.; Ko, S. Y. HCA 1991, 74, 1102.
13. (a) Burke, S. D.; Pacofsky, G. J.; Piscopio, A. D. TL 1986, 27, 3345. (b) Gioeli, C.; Balgobin, N.; Josephson, S.; Chattopadhyaya, J. B. TL 1981, 22, 969.
14. Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. TL 1981, 22, 4603; also see Ref. 3.
15. Sawabe, A.; Filla, S. A.; Masamune, S. TL 1992, 33, 7685.
16. Chao, H.-G.; Bernatowicz, M. S.; Klimas, C. E.; Matsueda, G. R. TL 1993, 34, 3377.
17. (a) Shute, R. E.; Rich, D. H. S 1987, 346. (b) Ref. 4. (c) Carpino, L. A.; Tsao, J.-H. CC 1978, 358.
18. Carpino, L. A.; Sau, A. C. CC 1979, 514.
19. Campbell, A. L.; Pilipauskas, D. R.; Khanna, I. K.; Rhodes, R. A. TL 1987, 28, 2331.
20. Marlin, J. E.; Killpack, M. O. H 1992, 34, 1385.
21. Oida, T.; Ohnishi, A.; Shimamaki, T.; Hayashi, Y.; Tanimoto, S. BCJ 1991, 64, 702.

Jayachandra P. Reddy

Indiana University, Bloomington, IN, USA

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