Trimethylsilyl ethers, protecting alcohols

Noyori and coworkers found that tetrafluorosilane or trimethylsilyl tri-flate catalyzes the condensation of appropriately protected glycopyranosyl fluorides with trimethylsilyl ethers or alcohols. The strong affinity of silicon for fluorine was considered to be the driving force for this reaction. In the case of Sip4, attack of a nucleophile on the glycosyl cation-SiFj ion-pair intermediate was anticipated. Thus, condensation of 2,3,4,6-tetra-O-benzyl-a- and - -D-glucopyranosyl fluorides (47a and 47fi) with methyl... 

The most stable protected alcohol derivatives are the methyl ethers. These are often employed in carbohydrate chemistry and can be made with dimethyl sulfate in the presence of aqueous sodium or barium hydroxides in DMF or DMSO. Simple ethers may be cleaved by treatment with BCI3 or BBr, but generally methyl ethers are too stable to be used for routine protection of alcohols. They are more useful as volatile derivatives in gas-chromatographic and mass-spectrometric analyses. So the most labile (trimethylsilyl ether) and the most stable (methyl ether) alcohol derivatives are useful in analysis, but in synthesis they can be used only in exceptional cases. In synthesis, easily accessible intermediates of medium stability are most helpful. 

Me3SiCH2CH=CH2i TsOH, CH3CN, 70-80°, 1-2 h, 90-95% yield. This silylating reagent is stable to moisture. Allylsilanes can be used to protect alcohols, phenols, and carboxylic acids there is no reaction with thiophenol except when CF3S03H is used as a catalyst. The method is also applicable to the formation of r-butyldimethylsilyl derivatives the silyl ether of cyclohexanol was prepared in 95% yield from allyl-/-butyldi-methylsilane. Iodine, bromine, trimethylsilyl bromide, and trimethylsilyl iodide have also been used as catalysts. Nafion-H has been shown to be an effective catalyst. 

Acetals are useful because they can act as protecting groups for aldehydes and ketones in the same way that trimethylsilyl ethers act as protecting groups for alcohols (Section 17.8). As we saw previously, it sometimes happens that one functional group interferes with intended chemistry elsewhere... 

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 are transformed by monofunctional silylating reagents Me3SiX 12 into their hpophilic and often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (=Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 °C). The persilylation of phenols and, in particular, catechol (or hydroquinone) systems (Scheme 2.1) protects them efficiently against air oxidation even at temperatures of up to 180 °C. (cf, e.g., the silylation-amination of purine nucleosides with dopamine hydrochloride in Section 4.2.4)... 

Protection of Alcohols. Trimethylsilyl ethers, readily prepared from alcohols by treatment with a variety of silylating agents have found considerable use for the protection of alcohols. They are thermally stable and reasonably stable to many organometallic reagents and they are easily cleaved by hydrolysis in acid or base or by treatment with fluoride ion. t, Butyl dimethylsilyl ethers have considerably greater hydrolytic stability and are easier to work with than trimethylsilyl ethers. They are prepared from alcohols by treatment with t. butyl dimethylsilyl chloride. 

Dicarboxypyridinium chlorochromate (2,6-DCPCC)392 possesses an acidic character that allows the in situ deprotection and oxidation of alcohols, protected as tetrahydropyranyl and trimethylsilyl ethers. 2,2 -Bipyridinium chlorochromate (BPCC)393 contains a ligand that complexes efficiently with the reduced chromium species, generated during the oxidation of alcohols, allowing for a substantial simplification of the work-ups. For this reason, it enjoys a popularity among chlorochromates surpassed by only PCC. 

Trimethylsilyl ethers.2 These protective derivatives of alcohols are conveniently prepared with K2COj or Na2C03 as base and Aliquat 336 as the phase-transfer catalyst (65 95% yield). r-Butyldimethylsilyl ethers can be prepared in the same way. 

If the alcohol 95 is protected as a trimethylsilyl ether and TMSOTf is employed as the Lewis acid, only catalytic amounts of Lewis acid have to be used (Scheme 13.39) [60]. Such a process is known in the literature under the name intramolecular silyl-modified Sakurai reaction (ISMS) [48],... 

The trimethylsilyl group has been used extensively for the protection of alcohols. One of the many methods which have been used for protecting a hydroxy group as its trimethylsilyl ether involves adding trimethylsilyl chloride (trimethylchlorosiiane, TMCS) to the alcohol in the presence of a weak base as exemplified in Equation Si2.1. 

The level of selectivity that can be achieved in the formation of trimethylsilyl ethers is illustrated by the selective protection of the hydroxy group at C-ll in the methyl ester of the prostaglandin 15-methyl PGF20 (Equation Si2.2). Thus the less sterically hindered secondary alcohol at C-ll is selectively protected in the presence of the more sterically hindered secondary alcohol at C-9 and the tertiary alcohol at C-15. 

Finally, alcohols can also be protected as silyl ethers. For example, the reaction of the alcohol with trimethylsilyl chloride in the presence of triethylamine (to react with the HC1 that is produced) produces the trimethylsilyl ether of the alcohol as shown in the following equation. (This reaction is a nucleophilic substitution by the oxygen on the silicon.) The silyl group can be removed in high yield by reaction with fluoride anion. 

TrimethylsiIylethanesulfonamides, to protect amines, 382-383 Trimethylsilyl (TMS) ethers to protect alcohols, 29, 68-71, 76, 77,... 

A ring expansion by two carbon atoms was discovered on heating (Z)-l-vinyl-cyclonon-3-en-l-yl-trimethylsilyl ether (V/62), Scheme V/10 [31] [32], Two types of trimethylsiloxy enol ethers were observed, each formed by a [1.3] or a [3.3] sigmatropic shift which, after hydrolysis, gave the ketones V/63, V/64, and V/65. The protection of the tertiary alcohol function is not necessary, if the reaction is done in the presence of potassium hydride [33] [34]. The reaction proceeds when the cyclic 1-vinyl alcohols have either a double bond or a benzo group at the 3-position. Other examples of this reaction type are given in Scheme V/10. 

Protection of hydroxyl groi. Trimethylsilyl ethers are too susceptible to solvolysis in protic media to be widely useful in synthesis. However, thedimethyl-/-butyl-silyloxy group is about 10 times more stable than the trimethylsilyloxy group. Dimethyl-/-butylchlorosilane reacts only slowly with alcohols in THF in the presence of excess pyridine. However, if imidazole (I, 492-494 2, 220) is used as catalyst and DMF as solvent, dimethyl-t-butylsilyl ethers arc obtained in high yield under mild conditions. N-Dimethyl-r-butylsilylimidazole is probably the actual silylating reagent. 

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