[75-77-4]  · C3H9ClSi  · Chlorotrimethylsilane  · (MW 108.64)

(protection of silyl ethers,3 transients,5-7 and silylalkynes;8 synthesis of silyl esters,4 silyl enol ethers,9,10 vinylsilanes,13 and silylvinylallenes;15 Boc deprotection;11 TMSI generation;12 epoxide cleavage;14 conjugate addition reactions catalyst16-18)

Alternate Names: trimethylsilyl chloride; TMSCl.

Physical Data: bp 57 °C; d 0.856 g cm-3.

Solubility: sol THF, DMF, CH2Cl2, HMPA.

Form Supplied in: clear, colorless liquid; 98% purity; commercially available.

Analysis of Reagent Purity: bp, NMR.

Purification: distillation over calcium hydride with exclusion of moisture.

Handling, Storage, and Precautions: moisture sensitive and corrosive; store under an inert atmosphere; use in a fume hood.

Protection of Alcohols as TMS Ethers.

The most common method of forming a silyl ether involves the use of TMSCl and a base (eqs 1-3).3,19-22 Mixtures of TMSCl and Hexamethyldisilazane (HMDS) have also been used to form TMS ethers. Primary, secondary, and tertiary alcohols can be silylated in this manner, depending on the relative amounts of TMS and HMDS (eqs 4-6).23

Trimethysilyl ethers can be easily removed under a variety of conditions,19 including the use of Tetra-n-butylammonium Fluoride (TBAF) (eq 7),20 citric acid (eq 8),24 or Potassium Carbonate in methanol (eq 9).25 Recently, resins (OH-and H+ form) have been used to remove phenolic or alcoholic TMS ethers selectively (eq 10).26

Transient Protection.

Silyl ethers can be used for the transient protection of alcohols (eq 11).27 In this example the hydroxyl groups were silylated to allow tritylation with concomitant desilylation during aqueous workup. The ease of introduction and removal of TMS groups make them well suited for temporary protection.

Trimethylsilyl derivatives of amino acids and peptides have been used to improve solubility, protect carboxyl groups, and improve acylation reactions. TMSCl has been used to prepare protected amino acids by forming the O,N-bis-trimethylsilylated amino acid, formed in situ, followed by addition of the acylating agent (eq 12).5 This is a general method which obviates the production of oligomers normally formed using Schotten-Baumann conditions, and which can be applied to a variety of protecting groups.5

Transient hydroxylamine oxygen protection has been successfully used for the synthesis of N-hydroxamides.6 Hydroxylamines can be silylated with TMSCl in pyridine to yield the N-substituted O-TMS derivative. Acylation with a mixed anhydride of a protected amino acid followed by workup affords the N-substituted hydroxamide (eq 13).6

Formation of Silyl Esters.

TMS esters can be prepared in good yields by reacting the carboxylic acid with TMSCl in 1,2-dichloroethane (eq 14).4 This method of carboxyl group protection has been used during hydroboration reactions. The organoborane can be transformed into a variety of different carboxylic acid derivatives (eqs 15 and 16).7 TMS esters can also be reduced with metal hydrides to form alcohols and aldehydes or hydrolyzed to the starting acid, depending on the reducing agent and reaction conditions.28

Protection of Terminal Alkynes.

Terminal alkynes can be protected as TMS alkynes by reaction with n-Butyllithium in THF followed by TMSCl (eq 17).8 A one-pot b-elimination-silylation process (eq 18) can also yield the protected alkyne.

Silyl Enol Ethers.

TMS enol ethers of aldehydes and symmetrical ketones are usually formed by reaction of the carbonyl compound with Triethylamine and TMSCl in DMF (eq 19), but other bases have been used, including Sodium Hydride29 and Potassium Hydride.30

Under the conditions used for the generation of silyl enol ethers of symmetrical ketones, unsymmetrical ketones give mixtures of structurally isomeric enol ethers, with the predominant product being the more substituted enol ether (eq 20).10 Highly hindered bases, such as Lithium Diisopropylamide (LDA),31 favor formation of the kinetic, less substituted silyl enol ether, whereas Bromomagnesium Diisopropylamide (BMDA)10 generates the more substituted, thermodynamic silyl enol ether. A combination of TMSCl/Sodium Iodide has also been used to form silyl enol ethers of simple aldehydes and ketones32 as well as from a,b-unsaturated aldehydes and ketones.33 Additionally, treatment of a-halo ketones with Zinc, TMSCl, and TMEDA in ether provides a regiospecific method for the preparation of the more substituted enol ether (eq 21).34

Mild Deprotection of Boc Protecting Group.

The Boc protecting group is used throughout peptide chemistry. Common ways of removing it include the use of 50% Trifluoroacetic Acid in CH2Cl2, Trimethylsilyl Perchlorate, or Iodotrimethylsilane (TMSI).19 A new method has been developed, using TMSCl-phenol, which enables removal of the Boc group in less than one hour (eq 22).11 The selectivity between Boc and benzyl groups is high enough to allow for selective deprotection.

In Situ Generation of Iodotrimethylsilane.

Of the published methods used to form TMSI in situ, the most convenient involves the use of TMSCl with NaI in acetonitrile.12 This method has been used for a variety of synthetic transformations, including cleavage of phosphonate esters (eq 23),35 conversion of vicinal diols to alkenes (eq 24),36 and reductive removal of epoxides (eq 25).37

Conversion of Ketones to Vinylsilanes.

Ketones can be transformed into vinylsilanes via intermediate trapping of the vinyl anion from a Shapiro reaction with TMSCl. Formation of either the tosylhydrazone38 or benzenesulfonylhydrazone (eq 26)13,39 followed by reaction with n-butyllithium in TMEDA and TMSCl gives the desired product.

Epoxide Cleavage.

Epoxides open by reaction with TMSCl in the presence of Triphenylphosphine or tetra-n-butylammonium chloride to afford O-protected vicinal chlorohydrins (eq 27).14

Formation of Silylvinylallenes.

Enynes couple with TMSCl in the presence of Li/ether or Mg/Hexamethylphosphoric Triamide to afford silyl-substituted vinylallenes. The vinylallene can be subsequently oxidized to give the silylated cyclopentanone (eq 28).15

Conjugate Addition Reactions.

In the presence of TMSCl, cuprates undergo 1,2-addition to aldehydes and ketones to afford silyl enol ethers (eq 29).16 In the case of a chiral aldehyde, addition of TMSCl follows typical Cram diastereofacial selectivity (eq 30).16,40

Conjugate addition of organocuprates to a,b-unsaturated carbonyl compounds, including ketones, esters, and amides, are accelerated by addition of TMSCl to provide good yields of the 1,4-addition products (eq 31).17,41,42 The effect of additives such as HMPA, DMAP, and TMEDA have also been examined.18,43 The role of the TMSCl on 1,2- and 1,4-addition has been explored by several groups, and a recent report has been published by Lipshutz.40 His results appear to provide evidence that there is an interaction between the cuprate and TMSCl which influences the stereochemical outcome of these reactions.

The addition of TMSCl has made 1,4-conjugate addition reactions to a-(nitroalkyl)enones possible despite the presence of the acidic a-nitro protons (eq 32).44 Copper-catalyzed conjugate addition of Grignard reagents proceeds in high yield in the presence of TMSCl and HMPA (eq 33).45 In some instances the reaction gives dramatically improved ratios of 1,4-addition to 1,2-addition.

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Ellen M. Leahy

Affymax Research Institute, Palo Alto, CA, USA

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