Silyl ether

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General structure of a silyl ether

Silyl ethers are a group of

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.

Common silyl ethers

TMS TES TBS/TBDMS TBDPS TIPS
Trimethylsilyl
ether
Triethylsilyl
ether
tert-Butyldimethylsilyl
ether 		tert-Butyldiphenylsilyl ether
Triisopropylsilyl
ether

Formation

Commonly

2,6-lutidine.[2]
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
.

Sometimes silyl

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.[3][4]

Removal

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.[5]

In acidic media, the relative resistance is:

TMS (1) < TES (64) < TBS (20 000) < TIPS (700,000) < TBDPS (5,000,000)

In basic media, the relative resistance is:

TMS (1) < TES (10-100) < TBS~TBDPS (20 000) < TIPS (100,000)

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:[6]

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 butyllithium:[7]

A third method uses a mixture of

DIPEA.[8]

Alternatively, an excess (4 eq) of the diol can be used, forcing the reaction toward monoprotection.

Selective deprotection

Selective deprotection of silyl groups is possible in many instances. For example, in the synthesis of

taxol:[9]

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.[10][11] 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.

Some common acidic conditions
  • 100 mol% 10-CSA (camphorsulfonic acid) in MeOH, room temperature; a "blast" of acid, deprotects primary TBS groups within ten minutes.
  • 10 mol% 10-CSA, 1:1 MeOH:DCM, −20 or 0 °C; deprotects a primary TBS group within two hours at 0; if CSA is replaced by
    p-TsOH
    , approximately ten times faster; solvent mixture is crucial.
  • 4:1:1 v/v/v AcOH:THF:water, room temp.; this is very slow, but can be very selective.
Some common basic conditions
  • HF-pyridine, 10:1 THF:pyridine, 0 °C; an excellent deprotection; removes primary TBS groups within eight hours; reactions using HF must be run in plastic containers.
  • TBAF, THF or 1:1
    TBAF/AcOH, THF; TBDPS and TBS groups can be deprotected in the presence of one another under different conditions.[12]

Application

References

  1. doi:10.1021/ja00772a043
  2. doi:10.1016/S0040-4039(01)81930-4
  3. ^ Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron: Asymmetry 1995, 6, 2503.
  4. ISSN 0957-4166
    .
  5. ISBN 9780471160199
    .
  6. doi:10.1021/jo00367a033
  7. doi:10.1021/jo00198a018
  8. doi:10.1016/S0040-4039(00)00626-2
  9. doi:10.1021/ja00083a067
  10. doi:10.1055/s-1996-4350
  11. doi:10.1016/j.tet.2004.04.042
  12. doi:10.1055/s-2000-7158

External links
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