Technical Library


The trimethylsilyl protecting group has been in use for many years. It is typically introduced via two common, commercially available reagents, namely, hexamethyldisilazane (HMDS) and chlorotrimethylsilane (TMS-Cl). When chlorotrimethylsilane is employed the resulting HCl by-product must be handled by off gassing or by trapping. Trapping is commonly done via the addition of triethylamine or pyridine. The reaction with HMDS liberates ammonia as the byproduct and this must be off-gassed or trapped in some way. It is normally off-gassed to a scrubber system. The reaction of HMDS is oftentimes quite slow, but can be catalyzed by the addition of one of several catalysts including TMS-Cl, ammonium chloride, or lithium chloride. Dimethylaminopyridine and imidazole have also been successfully employed as catalysts (Eq. 1).13 In addition to these very common and high-use reagents, the TMS group can be introduced with bis(trimethylsilyl)acetamide, BSA, or bis(trimethylsilyl)trifluoroacetamide, BSTFA, both of which give off a neutral byproduct, acetamide and trifluoroacetamide, respectively (Eq. 2).14

If greater reactivity and a more benign by-product are desired, one can turn to dimethylaminotrimethylsilane or N-trimethylsilylimidazole. Due to their excellent reactivity these reagents are commonly used to trimethylsilylate remaining non-silylated hydroxyls on the silica in the preparation of chromatography columns.

Trimethylsilyltriflate (TMS-OTf) is a very reactive silylating agent able to silylate most alcohols in high yield. The triflic acid by-product is typically trapped with a tertiary amine (Eq. 3).15

The various reagents available for the introduction of the TMS group are listed in Table 2. Deprotection of TMS ethers can be readily effected with dilute aqueous or methanolic HCl. TMS-protected alcohols have been selectively deprotected in the presence of a TES-protected alcohol.16,17 Nafion SAC-13 has been shown to be a recyclable catalyst for the trimethylsilylation of primary, secondary and tertiary alcohols in excellent yields and short reaction times.18

The triethylsilyl protecting group is primarily used for the protection of alcohols, although other groups including amines and carboxylic acids have been protected as their TES derivatives. A key consideration in the use of the TES protecting group is based on the generalization that its ease of removal falls between that of the more reactive TMS and the less reactive TBS groups. This presents various options for selective deprotection, which are often required in multi-step synthetic sequences.

The main reagent used for the preparation of triethylsilyl ethers is chlorotriethylsilane, TES-Cl. Since the triethylsilyl group is considerably more sterically hindered than the TMS group the usual protocol for its introduction is to employ a promoter such as imidazole, DMAP, or 2,6-lutidine to enhance the rate of silylation. Tertiary alcohols react very poorly with TES-Cl. Pyridine can also be used as a promoter. Alternatively, the triethylsilyltriflate TES-OTf can be used to introduce the triethylsilyl group. TES ethers can be selectively removed in the presence of TBS ethers.19

The combination of TES-Cl and pyridine selectively silylates a more hindered secondary alcohol over that of another secondary alcohol as shown in Eq. 4. This was employed in an efficient approach to a key intermediate for the synthesis of taxol derivatives. On the other hand, replacing the pyridine with imidazole results in the silylation of both secondary alcohols (Eq. 5).20

The direct triethylsilylation of alcohols in the presence of 2,6-lutidine as a promoter is accomplished with the use of TES-OTf in dichloromethane (Eq. 6).21

The TBS group is used for the protection of alcohols, amines, thiols, lactams, and carboxyl acids.22,23 The TBS group is typically introduced via the tert-butyldimethylchlorosilane, TBS-Cl, using imidazole, 2,6-lutidine or DMAP as promoters, though triethylamine can also be used (Eq. 7).22 The high stability of TBS-protected groups, in particular alcohols, to a variety of reaction conditions, its clean NMR characteristics and its facile removal with fluoride ion sources make it a popular choice among the silicon-based blocking agents. TBS ethers can be removed in the presence of TIPS and TBDPS ethers.24,25 Stork and Hudrlik initially illustrated the ability of the TBS group to form stable silyl enol ethers of ketones.26 An example of the use of TBS-Cl is shown in Eq. 7 and of TBS-OTf in Eq. 8.27,28

The thexyldimethylsilyl moiety was originally reported in 1985 for the highly stable protection of alcohols, amines, amides, mercaptans and acids.29 It can be introduced via reaction of the thexyldimethylchlorosilane, TDS-Cl, with promotion from triethylamine or imidazole in DMF, dichloromethane, or diethyl ether. Some examples, including one of a ketone to a TDS enol ether, are shown in Eqs. 9-11. The cyclodextrin 1 was selectively thexyldimethylsilylated at the C-6 alcohols to provide 2 in good yield (Eq. 12).30 Deprotection was accomplished with DIBAL-H.

The tert-butyldiphenylsilyl, TBDPS, group was first reported by Hanessian and Lavallee as a sterically hindered silylating agent with enhanced stability under acidic conditions.31 It is best introduced via the triflate (Eq. 13), but can also be introduced via the chloride (Eq. 14).32 Tert-butyldiphenylsilylated alcohols, indeed, show excellent stability under acidic conditions.

As with other silyl protecting groups the TBDPS group can be induced to migrate to a lesser sterically demanding position (Eq. 15).33

The triisopropylsilyl, TIPS, group is more sterically demanding than the TBS and TBDPS groups and can survive deprotection protocols that will remove these groups in its presence. It is a useful group for the protection of primary and secondary alcohols, although it reacts with secondary alcohols only under forcing conditions.34 It is essentially unreactive with tertiary alcohols and is typically introduced via the reaction of triisopropylchlorosilane, TIPS-Cl, or triisopropylsilyltriflate, TIPS-OTf, in the presence of a promoter such as imidazole or 2,6-lutidine (Eq. 16).35 Promotion with DMAP in pyridine appears to be a reactive combination, providing TIPS-protected secondary alcohols in good yields (Eqs. 17 & 18).36 Due to the bulky nature of the TIPS group it demonstrates excellent selectivity in the silylation of compounds with more than one hydroxyl group. TIPS-protected alcohols show excellent stability under basic conditions including n-butyllithium reactions.

Although the tert-butyldiphenylsilyl and triisopropylsilyl protecting groups offer excellent stability in terms of their resistance to an extensive variety of reaction conditions, there remains a need for an even more robust silicon-based protecting group in particular for groups other than the hydroxyl group. This would especially be true for the protection of amines and carboxylic acids. Professor E. J. Corey and coworkers have developed and studied a readily synthesized, very sterically demanding and stable organosilane blocking agent, namely, di-tert-butylisobutylsilyl trifluoromethanesulfonate, 3 BIBSOTf.37

In order to obtain good conversions of the substrates to the silylated derivatives with this severely stericallyl crowded organosilane the more reactive triflate form, 3, is required. In the silylation of alcohols typical reaction conditions are 65 °C in 1,4-dioxane in the presence of triethylamine and DMAP for several hours (Eq. 19). The reactivity depends strongly on the alcohol as well, with p-nitrophenol silylating nicely and phenol requiring the reaction of potassium phenoxide with BIBSOTf to get the phenoxysilane.

The silylation of primary amines with BIBSOTf proceeds well and in high yield, but secondary amines react very poorly and are best protected as the corresponding carbamates (Eq. 20).

The potassium enolate of ketones reacts with BIBSOTf to give the highly protected silyl enol ether again in high yield (Eq 21).

The silylating reagent BIBSOTf shows some intriguing chemoselectivities as illustrated by the products prepared below. For example, the selective protection of a primary amine over that of a primary aniline, a primary amine over that of a primary alcohol, a carboxylic acid over a primary alcohol, and the formation of a silyl enol ether over the silylation of a phenol are all possible as illustrated with the examples in Figure 3.

More recently a supersilyl group, tris(triethylsilyl)silyl, has been reported to provide highly stable silylated carboxylic acids (Eqs. 22 & 23). The supersilyl-silylated acids were shown to be stable to Grignard and organolithium reagents in addition to DIBAL-H and LiHMDS, however, they were not stable to methyllithium.38,39

The use of various silylene units such as the dimethyl-, DMS,40 diethyl-, DES,41 diisopropyl-, DIPS,42 di-tert-butyl-, DTBS,42,43 and diphenylsilylene, DPS,44 groups have been employed for the protection of diols, hydroxyacids, diamines, and similar difunctional systems. Here again, as expected, the more hindered the silicon center the more stable the silylated species becomes. Thus, the DTBS ethers of diols are hydrolytically stable between pH 4 and pH 10. The 6- and 7-membered ring systems from the silylene derivatives of 1,3- and 1,4-diols are more stable than the 5-membered rings resulting from the bridged silylation of 1,2-diols. The disilylethane derivative, tetramethyldisilylethane, STABASE, is used for the protection of primary amines, including those of esters of aminoacids.45 The tetraisopropyldisiloxanyl unit (from TIPDS) is highly useful for the protection of the 3’,5’-dihydroxyl moieties of nucleosides.46 The benzostabase, BSB, group can be used to protect primary aliphatic and aromatic amines.47,48

The commonly utilized silicon-based agents for the protection of diols and related functionalities such as diamines and hydroxy acids are shown in Figure 4.

The direct silylation of the triol 4 with di-tert-butylsilylbis(trifluoromethanesulfonate) results in the exclusive silylation of the C-4 and C-6 alcohols to form 5 (Eq. 24).49

Di-tert-butylsilylbis(triflate) was used in the synthesis of a double-protected sialic acid building block. This key building block was used to provide the sialylation of primary and secondary hydroxyl groups on galactosides (Eq. 25).50

In order to overcome the lability of the tetraisopropyldisiloxanyl-3’,5’-protected oligonucleotides, a bridging protecting group for this application, wherein the oxygen is replaced with a methylene group, was developed. This silyl protecting group proved to be equally selective in its reaction and much less labile under strong basic conditions required for the alkylation of the 2-hydroxyl group (Eq. 26).51