Silyl ether
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Silyl ethers are a group of chemical compounds sharing a common functional group in which a silicon atom is covalently bonded to an alkoxy group. The general structure is R1R2R3Si − O − R4 where R4 is an alkyl group or an aryl group. One way to form these ethers is by reaction of silyl halides with alcohols in the presence of an amine. Trimethylsilyl ethers can be obtained by reaction with hexamethyldisilazane, although more usually, they are made with chlorotrimethylsilane (TMSCl) or trimethylsilyl trifluoromethanesulfonate (TMSOTf). Silyl ethers are used as protecting groups in organic chemistry for instance as a trimethylsilyl ether (TMS), a tert-butyldiphenylsilyl ether (TBDPS), tert-butyldimethylsilyl ether (TBS/TBDMS) or a triisopropylsilyl ether (TIPS). Larger substituents increase resistance to hydrolysis, but also make introduction of the silyl group more difficult. Acid or fluorides such as tetra-n-butylammonium fluoride remove the silyl group when protection is no longer needed. In complex molecule syntheses, it is common for a large fraction of the molecular weight of the intermediate molecules leading up to the target molecule to comprise silyl protecting groups.
Stability to Cleavage
In acidic media, the relative stability is: TMS(1) < TES(64) < TBS (20 000) < TIPS (700 000) < TBDPS (5 000 000)
In basic media, the relative stability is: TMS (1) < TES(10-100) < TBS~TBDPS (20 000) < TIPS (100 000)
Standard Conditions for Formation
The formation of silyl ethers is considered extremely reliable, although their selective removal has occasionally been known to be problematic.
1. R3SiCl, Imidazole, DMF (standard Corey conditions, JACS 1972, 94, 6190)
2. R3SiOTf, 2,6-lutidine, DCM (for more hindered alcohols, TL 1981, 22, 3455)
A standard protocol for an unhindered alcohol calls for an overnight protection at room temperature. Usually, no special precautions are needed, although standard practice is to flame-dry the reaction vessel under vacuum and keep it under an inert atmosphere during the reaction. Purification involves the addition of ammonium chloride and water to quench and protonate any remaining base, followed by extraction. Since any excess or unreacted silylating agent is hydrolyzed to the corresponding trialkyl silanol (typically not removed by extraction), flash column chromatography is usually needed. The rather difficult to handle DMF called for in the Corey procedure can be directly replaced routinely with dichloromethane, with little or no effect on yield. This simplifies both reaction preparation and workup.
Monoprotection of Symmetrical Diols
It is possible to monosilylate a symmetrical diol, although this is known to be problematic occasionally. For example, the following monosilylation was reported (JOC 1986, 51, 3388):
However, it turns out that this reaction is hard to repeat. Statistically, if the dianion is of similar reactivity to the monoanion, then a corresponding statistical mixture of 1:2:1 disilylated:monosilylated:unsilylated diol will result. With sodium hydride, even allowing several hours for equilibration, poor results are usually obtained. Superior results are obtained with butyllithium:
Alternatively, an excess (4 eq) of the relatively cheap diol can be used, forcing the reaction toward monoprotection.
Selective Deprotection
Selective deprotection of silyl groups is possible in many instances. For example (JACS 1994, 116, 1599):
Unfortunately, usually extensive experimentation is required to determine optimal conditions. For example, 10-camphorsulfonic acid (CSA) has been used. Better results in selective deprotections are observed if CSA is used in 1:1 MeOH:DCM than if CSA is used in MeOH.
