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Silyl ether

April 11, 2024

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.

General structure of a silyl ether

Common silyl ethers edit

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

Formation edit

Commonly silylation of alcohols requires a silyl chloride and an amine base. One 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.[1] 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.[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 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 hindered 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.[3][4]

Removal edit

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 edit

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 DMF and DIPEA.[8]

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

Selective deprotection edit

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 PPTS, the rate is approximately ten times slower; with 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 edit

References edit

  1. ^ Corey, E. J.; Venkateswarlu, A. "Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives." J. Am. Chem. Soc. 1972, 94, 6190–6191. doi:10.1021/ja00772a043
  2. ^ Corey, E. J.; Cho, H.; Rücker C.; Hua, D. H. "Studies with trialkylsilyltriflates: new syntheses and applications." Tetrahedron Lett. 1981, 22, 3455–3458. doi:10.1016/S0040-4039(01)81930-4
  3. ^ Hayashi, T.; Hayashi, C.; Uozumi, Y. Tetrahedron: Asymmetry 1995, 6, 2503.
  4. ^ Hayashi, Tamio; Hayashi, Chihiro; Uozumi, Yasuhiro (1 October 1995). "Catalytic asymmetric hydrosilylation of ketones with new chiral ferrocenylphosphine-imine ligands". Tetrahedron: Asymmetry. 6 (10): 2503–2506. doi:10.1016/0957-4166(95)00326-K. ISSN 0957-4166.
  5. ^ Greene, T. W.; Wuts, P. G. M. (1999). Protective Groups in Organic Synthesis. New York: John Wiley & Sons. p. 114. ISBN 9780471160199.
  6. ^ McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. "A convenient procedure for the monosilylation of symmetric 1,n-diols." J. Org. Chem. 1986, 51, 3388–3390. doi:10.1021/jo00367a033
  7. ^ Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. "Hydrofluoric acid catalyzed intramolecular Diels-Alder reactions " J. Org. Chem. 1983, 49, 4674–4682. doi:10.1021/jo00198a018
  8. ^ Hu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, 4281. doi:10.1016/S0040-4039(00)00626-2
  9. ^ Holton, R. A. et al. "First total synthesis of taxol. 2. Completion of the C and D rings." J. Am. Chem. Soc. 1994, 116, 1599–1600. doi:10.1021/ja00083a067
  10. ^ Nelson, T. D.; Crouch, R. D. "Selective deprotection of silyl ethers." Synthesis 1996, 1031–1069. doi:10.1055/s-1996-4350
  11. ^ Crouch, R. D. "Selective monodeprotection of bis-silyl ethers." Tetrahedron 2004, 60, 5833–5871. doi:10.1016/j.tet.2004.04.042
  12. ^ Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.; Nakata, M. "Selective deprotection of t-butyldiphenylsilyl ethers in the presence of t-butyldimethylsilyl ethers by tetrabutylammonium fluoride, acetic acid, and water." Synlett 2000, 1306–1308. doi:10.1055/s-2000-7158

External links edit

  • Example deprotection TBS silyl ether
  • Example deprotection TBDMS silyl ether
  • silyl ether formation in carbohydrates

April 11, 2024
silyl, ether, group, chemical, compounds, which, contain, silicon, atom, covalently, bonded, alkoxy, group, general, structure, r1r2r3si, where, alkyl, group, aryl, group, usually, used, protecting, groups, alcohols, organic, synthesis, since, r1r2r3, combinat. 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 General structure of a silyl ether Contents 1 Common silyl ethers 2 Formation 3 Removal 4 Monoprotection of symmetrical diols 5 Selective deprotection 6 Application 7 References 8 External linksCommon silyl ethers edit nbsp nbsp nbsp nbsp nbsp TMS TES TBS TBDMS TBDPS TIPSTrimethylsilyl ether Triethylsilyl ether tert Butyldimethylsilyl ether tert Butyldiphenylsilyl ether Triisopropylsilyl etherFormation editCommonly silylation of alcohols requires a silyl chloride and an amine base One 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 1 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 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 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 hindered 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 3 4 Removal editReaction 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 lt TES 64 lt TBS 20 000 lt TIPS 700 000 lt TBDPS 5 000 000 In basic media the relative resistance is TMS 1 lt TES 10 100 lt TBS TBDPS 20 000 lt TIPS 100 000 Monoprotection of symmetrical diols editIt is possible to monosilylate a symmetrical diol although this is known to be problematic occasionally For example the following monosilylation was reported 6 nbsp 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 nbsp A third method uses a mixture of DMF and DIPEA 8 Alternatively an excess 4 eq of the diol can be used forcing the reaction toward monoprotection Selective deprotection editSelective deprotection of silyl groups is possible in many instances For example in the synthesis of taxol 9 nbsp 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 conditions100 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 PPTS the rate is approximately ten times slower with 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 conditionsHF 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 editThis section is empty You can help by adding to it June 2023 References edit Corey E J Venkateswarlu A Protection of hydroxyl groups as tert butyldimethylsilyl derivatives J Am Chem Soc 1972 94 6190 6191 doi 10 1021 ja00772a043 Corey E J Cho H Rucker C Hua D H Studies with trialkylsilyltriflates new syntheses and applications Tetrahedron Lett 1981 22 3455 3458 doi 10 1016 S0040 4039 01 81930 4 Hayashi T Hayashi C Uozumi Y Tetrahedron Asymmetry 1995 6 2503 Hayashi Tamio Hayashi Chihiro Uozumi Yasuhiro 1 October 1995 Catalytic asymmetric hydrosilylation of ketones with new chiral ferrocenylphosphine imine ligands Tetrahedron Asymmetry 6 10 2503 2506 doi 10 1016 0957 4166 95 00326 K ISSN 0957 4166 Greene T W Wuts P G M 1999 Protective Groups in Organic Synthesis New York John Wiley amp Sons p 114 ISBN 9780471160199 McDougal P G Rico J G Oh Y I Condon B D A convenient procedure for the monosilylation of symmetric 1 n diols J Org Chem 1986 51 3388 3390 doi 10 1021 jo00367a033 Roush W R Gillis H R Essenfeld A P Hydrofluoric acid catalyzed intramolecular Diels Alder reactions J Org Chem 1983 49 4674 4682 doi 10 1021 jo00198a018 Hu L Liu B Yu C Tetrahedron Lett 2000 41 4281 doi 10 1016 S0040 4039 00 00626 2 Holton R A et al First total synthesis of taxol 2 Completion of the C and D rings J Am Chem Soc 1994 116 1599 1600 doi 10 1021 ja00083a067 Nelson T D Crouch R D Selective deprotection of silyl ethers Synthesis 1996 1031 1069 doi 10 1055 s 1996 4350 Crouch R D Selective monodeprotection of bis silyl ethers Tetrahedron 2004 60 5833 5871 doi 10 1016 j tet 2004 04 042 Higashibayashi S Shinko K Ishizu T Hashimoto K Shirahama H Nakata M Selective deprotection of t butyldiphenylsilyl ethers in the presence of t butyldimethylsilyl ethers by tetrabutylammonium fluoride acetic acid and water Synlett 2000 1306 1308 doi 10 1055 s 2000 7158External links editExample deprotection TBS silyl ether Example deprotection TBDMS silyl ether Silicon based Protection of the Hydroxyl Group silyl ether formation in carbohydrates Retrieved from https en wikipedia org w index php title Silyl ether amp oldid 1196066734, wikipedia, wiki, book, books, library,

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