2-(Trimethylsilyl)ethoxymethyl Chloride1

[76513-69-4]  · C6H15ClOSi  · 2-(Trimethylsilyl)ethoxymethyl Chloride  · (MW 166.75)

(protection of alcohols,1,2 secondary aryl amines,3 and imidazole, indole, and pyrrole nitrogens;4-6 electrophilic formaldehyde equivalent;7 acyl anion equivalent8)

Alternate Name: SEM-Cl.

Physical Data: bp 57-59 °C/8 mmHg; d 0.942 g cm-3.

Solubility: sol most organic solvents (pentane, CH2Cl2, Et2O, THF, DMF, DMPU, HMPA).

Form Supplied in: liquid; commercially available 90-95% pure; HCl is typical impurity.

Analysis of Reagent Purity: GC.

Preparative Methods: several syntheses have been reported.2,9 -12

Handling, Storage, and Precautions: water sensitive; corrosive; should be stored in a glass container under an inert atmosphere; a lachrymator; flammable (fp 46 °C).

Reagent for the Protection of Alcohols.

Lipshutz and co-workers introduced the use of SEM-Cl for the protection of primary, secondary, and tertiary alcohols (eq 1).2 SEM-Cl is now widely employed in organic synthesis for the protection of hydroxyl functionalities (eqs 2 and 3).13,14

The resulting SEM ethers are stable under a variety of conditions. Most SEM ethers are cleaved with a fluoride anion source (eqs 4 and 5),2,15-17 although this fragmentation is generally much less facile than fluoride-induced cleavage of silyloxy bonds. Therefore the selective deprotection of other silyl ethers in the presence of SEM ethers is possible (eq 6).15 Vigorous conditions with anhydrous fluoride ion are required for the cleavage of some tertiary SEM ethers (eq 7).18,19

The stability of SEM ethers has necessitated the development of a variety of other deprotection methods. SEM protective groups are stable to the acidic conditions used to hydrolyze THP, TBDMS, and MOM ethers (AcOH, H2O, THF, 45 °C),2 but can be removed under strongly acidic conditions with Trifluoroacetic Acid.20 SEM, MTM, and MOM ethers are selectively cleaved in the presence of MEM, TBDMS, and benzyl ethers with Magnesium Bromide (eq 8).21 SEM, MOM, and MEM phenolic protective groups are removed with Diphosphorus Tetraiodide (eq 9).22

SEM-Cl has also proven useful in carbohydrate synthesis where the resulting SEM ethers can be cleaved under less acidic conditions than those required for the cleavage of MOM and MEM ethers (eq 10).23

Reagent for the Protection of Acids.

Carboxylic acids can be protected as SEM esters (eq 11).24,25 Cleavage of the SEM esters occurs with refluxing methanol24 or magnesium bromide (eq 12).25,26

Reagent for the Protection of Secondary Amines.

SEM-Cl can be used to protect secondary aromatic amines (eq 13),3 and is an ideal reagent for the protection of imidazoles, indoles, and pyrroles (eqs 14-16).4-6,27 Many functional groups are compatible with the introduction and cleavage of SEM amines, and the SEM substituent is unusually stable to further functionalization of the molecule.4-6,27 Recently, a one-pot method for protection and alkylation of imidazoles employing n-Butyllithium and SEM-Cl has been developed (eq 17).28-30

One-Carbon Homologations.

SEM-Cl has functioned as an alternative to the use of Formaldehyde (eq 18).7 The enolate of the lactone (1) undergoes C-alkylation with SEM-Cl, and the resulting SEM substituent can be subsequently treated with trifluoroacetic acid to afford the alcohol (2).

SEM-Cl has been transformed to a formaldehyde carbanion equivalent.8 SEM-Cl is converted to the ylide upon treatment with Triphenylphosphine and Sodium Hydride. This ylide reacts with a variety of aldehydes and ketones affording enol ethers (eq 19).8 Hydrolysis with 5% aqueous HF gives the corresponding aldehyde.

1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991.
2. Lipshutz, B. H.; Pegram, J. J. TL 1980, 21, 3343.
3. Zeng, Z.; Zimmerman, S. C. TL 1988, 29, 5123.
4. Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. JOC 1986, 51, 1891.
5. Ley, S. V.; Smith, S. C.; Woodward, P. R. T 1992, 48, 1145.
6. Muchowski, J. M.; Solas, D. R. JOC 1984, 49, 203.
7. Baldwin, J. E.; Lee, V.; Schofield, C. J. SL 1992, 249.
8. Schönauer, K.; Zbiral, E. TL 1983, 24, 573.
9. Sonderquist, J. A.; Hassner, A. JOM 1978, 156, C12.
10. Sonderquist, J. A.; Thompson, K. L. JOM 1978, 159, 237.
11. Gerlach, H. HCA 1977, 60, 3039.
12. Fessenden, R. J.; Fessenden, J. S. JOC 1967, 32, 3535.
13. Kotecha, N. R.; Ley, S. V.; Mantegani, S. SL 1992, 395.
14. Lipshutz, B. H.; Moretti, R.; Crow, R. TL 1989, 30, 15.
15. Williams, D. R.; Jass, P. A.; Tse, H.-L. A.; Gaston, R. D. JACS 1990, 112, 4552.
16. Shull, B. K.; Koreeda, M. JOC 1990, 55, 99.
17. Ireland, R. E.; Varney, M. D. JOC 1986, 51, 635.
18. Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. TL 1988, 29, 5417.
19. Lipshutz, B. H.; Miller, T. A. TL 1989, 30, 7149.
20. Schlessinger, R. H.; Poss, M. A.; Richardson, S. JACS 1986, 108, 3112.
21. Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. SL 1991, 183.
22. Saimoto, H.; Kusano, Y.; Hiyama, T. TL 1986, 27, 1607.
23. Pinto, B. M.; Buiting, M. M. W.; Reimer, K. B. JOC 1990, 55, 2177.
24. Logusch, E. W. TL 1984, 25, 4195.
25. Kim, S; Park, Y. H.; Kee, I. S. TL 1991, 32, 3099.
26. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. T 1993, 49, 3691.
27. Lipshutz, B. H.; Vaccaro, W.; Huff, B. TL 1986, 27, 4095.
28. Lipshutz, B. H.; Huff, B.; Hagen, W. TL 1988, 29, 3411.
29. Demuth, T. P., Jr.; Lever, D. C.; Gorgos, L. M.; Hogan, C. M.; Chu, J. JOC 1992, 57, 2963.
30. For a similar method with pyrroles, see Ref. 13.

Jill Earley

Indiana University, Bloomington, IN, USA

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