Silyl ether

Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis. Since R1R2R3 can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compounds provides a wide spectrum of selectivity for protecting group chemistry. Common silyl ethers are: trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS) and triisopropylsilyl (TIPS). They are particularly useful because they can be installed and removed very selectively under mild conditions. Although many methods are available for forming silyl ethers, two common strategies for the silylation of alcohols are: reaction of the alcohol with a silyl chloride using an amine base at room temperature and reaction of the alcohol with a silyl triflate using a hindered amine base at low temperature. Silyl triflates are more reactive than their corresponding chlorides, so they can be used to install silyl groups onto hindered positions. One extremely reliable and rapid procedure is the Corey protocol in which the alcohol is reacted with a silyl chloride and imidazole at high concentration in DMF. If DMF is replaced by dichloromethane, the reaction is somewhat slower, but the purification of the compound is simplified. A common hindered base for use with silyl triflates is 2,6-lutidine. Primary alcohols can be protected in less than one hour while some hindered alcohols may require days of reaction time. When using a silyl chloride, no special precautions are usually required, except for the exclusion of large amounts of water. An excess of silyl chloride can be employed but is not necessary. If excess reagent is used, the product will require flash chromatography to remove excess silanol and siloxane. Silyl triflates are water sensitive and must be run under inert atmosphere conditions. Purification involves the addition of an aqueous acid such as saturated ammonium chloride solution. This quenches remaining silyl reagent and protonates amine bases, removing them from the reaction mixture. Following extraction, the product can be purified by flash chromatography. Silyl triflate is more reactive and also converts ketones to silyl enol ethers. Reaction with acids or fluorides such as tetra-n-butylammonium fluoride removes the silyl group when protection is no longer needed. Larger substituents increase resistance to hydrolysis, but also make introduction of the silyl group more difficult.