Product Code Database
Silyl ethers are a group of chemical compounds which contain a silicon atom covalent bond 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.
| RO(TMS) | RO(TES) | RO(TBS)/RO(TBDMS) | RO(TBDPS) | RO(TIPS) |
| Trimethylsilyl ether | Triethylsilyl ether | tert-Butyldimethylsilyl ether | tert-Butyldiphenylsilyl ether | Triisopropylsilyl ether |
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.
Sometimes silyl triflate and a hindered amine base are used. Silyl triflates are more reactive than their corresponding chlorides, so they can be used to install silyl groups onto Steric hindrance positions. Silyl triflate is more reactive and also converts ketones to silyl enol ethers. 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. Water quenches remaining silyl reagent and protonates amine bases prior to their removal from the reaction mixture. Following extraction, the product can be purified by flash chromatography.
Ketones react with hydrosilanes in the presence of metal catalysts.Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron: Asymmetry 1995, 6, 2503.
In acidic media, the relative resistance is:
In basic media, the relative resistance is:
However, it turns out that this reaction is hard to repeat. If the reaction were controlled solely by thermodynamics, and if the dianion is of similar reactivity to the monoanion, then a corresponding statistical mixture of 1:2:1 disilylated:monosilylated:unsilylated diol would be expected. However, the reaction in THF is made selective by two factors: 1. kinetic deprotonation of the first anion and 2. the insolubility of the monoanion. At the initial addition of TBSCl, there is only a minor amount of monoanion in solution with the rest being in suspension. This small portion reacts and shifts the equilibrium of the monoanion to draw more into solution, thereby allowing for high yields of the mono-TBS compound to be obtained. Superior results in some cases may be obtained with N-Butyllithium:Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. "Hydrofluoric acid catalyzed intramolecular Diels-Alder reactions " J. Org. Chem. 1983, 49, 4674–4682.
A third method uses a mixture of DMF and DIPEA.Hu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, 4281.
Alternatively, an excess (4 eq) of the diol can be used, forcing the reaction toward monoprotection.
Silyl ethers are mainly differentiated on the basis of sterics or electronics. In general, acidic deprotections deprotect less hindered silyl groups faster, with the steric bulk on silicon being more significant than the steric bulk on oxygen. Fluoride-based deprotections deprotect electron-poor silyl groups faster than electron-rich silyl groups. There is some evidence that some silyl deprotections proceed via hypervalent silicon species.
The selective deprotection of silyl ethers has been extensively reviewed.Nelson, T. D.; Crouch, R. D. "Selective deprotection of silyl ethers." Synthesis 1996, 1031–1069. Crouch, R. D. "Selective monodeprotection of bis-silyl ethers." Tetrahedron 2004, 60, 5833–5871. Although selective deprotections have been achieved under many different conditions, some procedures, outlined below, are more reliable. A selective deprotection will likely be successful if there is a substantial difference in sterics (e.g., primary TBS vs. secondary TBS or primary TES vs primary TBS) or electronics (e.g. primary TBDPS vs. primary TBS). Unfortunately, some optimization is inevitably required and it is often necessary to run deprotections partway and recycle material.
|
|
