N,O-Bis(trimethylsilyl)acetamide

[10416-59-8]  · C8H21NOSi2  · N,O-Bis(trimethylsilyl)acetamide  · (MW 203.43)

(powerful silylating agent; reacts with a wide range of functional groups)

Alternate Name: BSA.

Physical Data: bp 71-73 °C/35 mmHg.1,2

Solubility: very sol most organic solvents.

Form Supplied in: liquid; rapidly contaminated with trimethylsilylacetamide and acetamide if exposed to moist air. Drying: extreme moisture sensitivity; should be kept in a sealed container.

Preparative Method: made by the reaction of acetamide with a large excess of Chlorotrimethylsilane in the presence of Triethylamine.1,2

Handling, Storage, and Precautions: no special handling and storage procedures; all work must be carried in an efficient fume hood.

Bis(trimethylsilyl)acetamide.

Bis(trimethylsilyl)acetamide (BSA) has been formulated as N,N-bis(trimethylsilyl)acetamide as well as the imidate form. The NMR spectra of a number of silylamide derivatives (13C, 29Si, 14N, and 17O) have been investigated. Whereas BSA is seen to exist in the imidate form, some analogs, for example bis(trimethylsilyl)formamide, exist in the N,N-bis(trimethylsilyl) form, and the product obtained by the interaction of 1,2-Bis(chlorodimethylsilyl)ethane with BSA is also clearly in the alternative form.3 Trimethylsilyl derivatives of hydroxamic acids are formed in reactions using Hexamethyldisilazane and are similar in structure to BSA.4 This entry will concentrate on examples from the more recent literature.

Protection of Functional Groups.

Early reports of the use of BSA concentrated on the preparation of derivatives of a number of functional group types in order to facilitate chromatographic analysis. The trimethylsilylation of amides, ureas, amino acids and dipeptides, carboxylic acids, enols and hindered phenols were reported under mild reaction conditions.1,2 Substituted ureas are converted into their monosilylated derivatives because of the lone electron pair involvement and so N,N-Bis(trimethylsilyl)urea is close in energy to BSA. By the same token, one of the trimethylsilyl residues in BSA is replaced more easily than the second. The conversion of N-haloamides into the N-haloimidic trimethylsilyl esters, for example N-chloroacetamide into N-chloroacetimidic trimethylsilyl ester, was probably the first reported use of BSA.5 Part per billion traces in water of environmentally important phenols and carboxylic acids have been determined by concentration using macroreticular resins and subsequent derivatization using BSA before gas chromatography.6 It has been claimed that trimethylsilylation of trichothecines prior to gas chromatography is best achieved by using bis(trimethylsilyl)trifluoroacetamide (BSTFA) rather than BSA.7

Protection of Hydroxy Groups.

The first example of the use of the trimethylsilyl group for the protection of a sterically hindered hydroxy group involved a 14-hydroxy steroid which was treated with bis(trimethylsilyl)acetamide in DMF at 78 °C.8 Since that time a wide variety of alcohols have been protected using BSA. The product from the enantioselective hydroboration-oxidation of N-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine was converted into its trimethylsilyl ether (TMS ether) in order to allow isolation by gas chromatography.9 The osmylation of unsaturated ester components of insect pheromones, followed by a reductive workup and silylation with BSA, has been used to allow identification using GC-MS.10 Bis(trimethylsilylation) using BSA has been shown to be the most convenient method for the protection of a range of biologically important dihydroarenediols prior to characterization using GC-MS.11 High yields have been reported with other secondary alcohols using BSA,12 including the example shown in eq 1.13 The method has been used to effect the trimethylsilylation of an aldol product,14 Ninhydrin reacts with allyltrimethylsilane and trimethylsilyl triflate in acetonitrile to give the expected 2,2-bis(trimethylsilyloxy)indan-1,3-dione. However, using BSA the major product incorporated an acetamido residue.15 The replacement of an acetoxy group by an amido group (eq 2) presumably occurs via an oxonium species.16

Bis(trimethylsilyl)acetamide has also been used to provide temporary protection of hydroxy and carboxy groups in a number of coupling reactions involved in the preparation of cephalosporins and penicillins, as shown in eq 3.17 The protection of nucleoside hydroxy groups prior to reduction using tributyltin hydride-AIBN has been reported.18 The same method has also been used in connection with nucleoside coupling reactions.19 Transglycosylation catalyzed by trimethylsilyl triflate has also been carried out on trimethylsilyl-protected nucleosides (eq 4), in which the prior protection was effected using BSA.20 In the case of 6-oxopurineribonucleoside synthesis, the 7b-isomer is first formed and eventually affords the 9b-isomer, presumably by way of the 7,9-diribonucleoside.21 It has been shown that BSA causes the debromination of some purine nucleosides in the presence of Potassium Fluoride and a crown ether.22

The silylation of tertiary alcohols in good yields has been reported, e.g. di-t-hydroxyadamantane.23 The preparation of 2-methyl-2-trimethylsilyloxynonadecane was achieved in 84% yield using a combination of BSA, chlorotrimethylsilane, and N-(Trimethylsilyl)imidazole.24 2-Methyl-2-trimethylsilyloxypentanone, a prototype for a series of compounds that are valuable intermediates used in a study of diastereoselective aldol reactions, can be prepared in good yield using BSA.25 Even highly hindered silanols react with BSA as indicated in eq 5.26 It is of interest to note that BSA has been used to reduce the influence of free hydroxy groups on surfaces. Difficult Diels-Alder reactions that require high temperatures and are carried out in sealed glass tubes may suffer from decomposition of the diene on the surface of the glass. Silylation with BSA is then worth investigating.27 It has also been shown that the charcoal carrier for tungstic acid-Tri-n-butylchlorostannane, which is used in the catalyzed hydrogen peroxide epoxidation of alkenes, is improved by treatment with BSA. Decomposition of the hydrogen peroxide, catalyzed by surface hydroxy groups, is then less troublesome.28

Formation of Trimethylsilyl Enol Ethers.

The silylation of enolizable aldehydes and ketones has been carried out using BSA in HMPA in the presence of very small amounts of metallic sodium. The method is highly regio- and stereoselective, giving the (Z)-isomer that results from kinetic control.29 With more easily enolized compounds the reaction proceeds readily in the absence of other additives. In the case of the bis(trimethylsilylation) of oxindole (eq 6) the effect is evidently related to the gain in resonance energy on silylation at oxygen.2 Similarly, the conversion of glutaconic anhydride into the silylated a-pyrone (eq 7) was achieved in very high yield using BSA.30 The product is a very useful Diels-Alder diene. Other highly functionalized dienes have been prepared and used in Diels-Alder syntheses of highly functionalized naturally occurring anthraquinones. The dienes shown in eqs 8 and 9 were used in the syntheses of ceroalbolinic acid31 and xantholaccaic acid,32 respectively.

The protection of phenols was one of the first examples of the use of BSA, including the trimethylsilylation of 2,6-di-t-butylphenol.2 2,6-Di-t-butyl-4-vinylphenol has been protected with BSA and then polymerized by both cationic and radical initiators before liberating the free phenolic groups by cleavage with acid.33 A number of calixarene trimethylsilyl ethers have been prepared from the phenols using BSA.34 Calix[4]arene has been converted into a mixture of tris- and tetrakis(trimethylsilyl) ethers by heating the phenol with BSA in acetonitrile.35

Protection of Carboxy Groups.

As with hydroxy compounds, the conversion of carboxy groups into their trimethylsilyl derivatives is valuable in connection with GC-MS. The method has been used, for example, in assaying a perhydroindole ACE inhibitor.36 Amino acid hydrohalides are silylated in almost quantitative yields by BSA in THF at reflux. Other methods require higher temperatures. The free amino acid can be isolated after treatment with water and another important feature is that no racemization was observed.37 The use of BSA in peptide coupling reactions has been reported,38 including examples where hydroxy amino acids are involved.39 A coupling reaction involved in a total synthesis of the immunostimulating peptide FK156 also involved the formation of a peptide TMS ester.40 The trimethylsilylation of (E)-3-bromoacrylic acid proceeds in good yield (eq 10) and has been used in conjunction with a protected alanyl anion in the synthesis of an unsaturated a-amino acid.41 The bis(trimethylsilyl) ester of squaric acid, formed using BSA (eq 11), has been shown to be in dynamic equilibrium. The trimethylsilyl groups undergo rapid intermolecular migration, as established by crossover experiments.42

Reactions at Nitrogen.

The protection and activation of a number of nitrogen functional groups has been achieved using BSA, for example the silylation of aziridines.43 Treatment of primary and secondary amines with BSA and then with a chloroformate gives good yields of carbamates.44 Conversion of the guanine derivative into the bis(trimethylsilyl) derivative and the Trimethylsilyl Trifluoromethanesulfonate nucleoside coupling reaction (eq 12) was part of a synthesis of AzddMAP.45 Similarly, the conversion of sulfoximines into their TMS derivatives, prior to deprotonation and reaction with a range of electrophiles, can be carried out in almost quantitative yields using BSA.46 The preparation of the 1,3,4-oxadiazoline shown in eq 13 was achieved in 60-65% yield.47

The increased volatility on silylation of pyrimido[4,5-i]imidazo[4,5-g]cinnoline has been investigated in connection with flash vacuum pyrolysis studies.48 It has been reported that dihydropyrimidines and dihydro-s-triazines were dehydrogenated under vigorous trimethylsilylation conditions.49 Apparently the reaction does not proceed in the absence of oxygen or in the presence of free radical inhibitors. Aromatic isocyanates react with BSA to give silylated azauracils as shown in eq 14, which are desilyated on treatment with ethanol.50 We also note that BSA and other bis(trimethylsilyl)amides are converted into nitriles in high yields by treatment with Tetra-n-butylammonium Fluoride. Lewis acids, or Iron(II) Phthalocyanine,51 and a range of bis(trimethylsilyl)amides react with Phosgene to form acyl isocyanates.52 Arylsulfonylacetonitriles undergo carbon-carbon coupling reactions when heated in BSA at 120-140 °C.53 A range of silylnitronates have been prepared using BSA or the trifluoro analog (BSTFA). The products (eq 15) are useful intermediates for the synthesis of isoxazolidines.54

The Control of Protic Acids.

There are a number of examples where protic acids have been shown to have a deleterious effect on reactions and where partial or complete control is advantageous. The rearrangement of the benzylpenicillin sulfoxide to the cephalosporanic acid derivative (eq 16) gave the best yield using Hydrogen Bromide and ca. 30 mol % of BSA.55 Similarly, the preparation of eight-membered oxygen heterocycles that are present in a number of marine natural products, has been achieved in moderate yields by Lewis acid promoted acetal-alkene cyclizations in the presence of BSA as shown in eq 17.56 The same principle has been used to control Friedel-Crafts alkylation reactions involving, for example, methyl chloromethoxyacetate and N-methylindole.57 In the absence of BSA a considerable amount of the indole derivative was converted into its dimer while the major product was methyl bis(1-methyl-3-indolyl)acetate. In the presence of BSA the formation of the dimer was suppressed and the initial product, methyl 1-methyl-3-indolylacetate, isolated in a 90% yield. Control in the highly diastereoselective alkylation of 1-methylindole using chiral pyrrole derivatives was achieved in a better yield when using BSA (eq 18).58

Use has also been made of the oxophilicity of silicon, as compared to the azaphilicity of protons, in Mannich reactions of bis(aminol ethers) with heterocycles such as 2-methylfuran where a proton is liberated during the reaction.59 The bis(methoxymethyl) derivative from t-butylamine gave an iminium salt when treated with hydrogen chloride in ether. In duplicate reactions using 2-methylfuran, one (eq 19) was treated with BSA while the other, in the absence of BSA, was worked up using Hünig's base and gave the expected secondary amine after a hydrolytic work up in 80% yield. Evidently in the first reaction the BSA reacted with the hydrogen chloride produced and gave chlorotrimethylsilane.

The reaction between triflic acid and N-trimethylsilyl-1,3-oxazolidin-2-one has been shown to afford trimethylsilyl triflate in a high yield, whereas the reaction of BSA with triflic acid gave only a 43% yield of trimethylsilyl triflate.60 Despite that finding, in situ catalytic reactions involving trimethylsilyl triflate (eq 20)58b and trimethylsilyl fluorosulfonate (eq 21)61 can be carried out in high yields when a catalytic amount of the acid is added to BSA.

Reactions of the Anion from Bis(trimethylsilyl)acetamide.

The deprotonation of BSA using Lithium Diisopropylamide was used to generate the protected acetamide enolate ion for use in the synthesis of the dienone shown in eq 22.62 It has been shown subsequently that the same product can be prepared by the reaction of the anion, generated from n-butyllithium and BSA, with 2,6-dibromo-1,4-benzoquinone.63 The anion has also been used in reactions with a number of carbonyl compounds, including benzophenone.64

Reactions of Phosphorus Compounds.

A number of papers report the conversion of chlorophosphites, dichlorophosphites, and their thio analogs into trimethylsilyl derivatives.65 The reaction between bromodifluorophosphine and BSA at -80 °C results in formation of an unstable product with a P-N bond together with bromotrimethylsilane.66 Nucleoside phosphonates have been converted into the related bis(trimethylsilyl) phosphites by treatment with BSA. Subsequent reaction with an acyl chloride and triethylamine then rapidly affords the corresponding acyl phosphonate.67 The Michael addition of phosphonous acids and esters by way of intermediate silyl alkyl phosphonites has been used in the preparation of phosphinic acids (eq 23).68 The coupling of an activated acid with an acylphosphoranylidene in the presence of BSA (eq 24) has been used in the synthesis of the vicinal tricarbonyl portion of the immunosuppressant macrocyclic lactone FK-506.69 The coupling in that case gave the required product in a 91% yield.

Metal Catalyzed Reactions of Allylic Esters.

Hexacarbonylmolybdenum catalyzed elimination of acetic acid in the presence of BSA is effective in a high yield route to conjugated dienes,70 and BSA has been used as a base in an unexpected palladium catalyzed tandem elimination-cycloaddition reaction.71 The alkylation of malonic esters with allylic acetates using hexacarbonyl molybdenum and BSA (eq 25) has been reported to give high yields.72 b-Keto esters are also alkylated using palladium(0) catalysis. In reactions of 2-hydroxymethyl-2-propen-1-ol diacetate with methyl 4-methylcyclohexanone-2-carboxylate, the use of BSA gave the monoalkylated product whereas using DBU resulted in the formation of the bicycloannulation product.73 The palladium catalyzed alkylation of sodium dimethyl malonate with a silylated allene acetate in the presence of BSA (eq 26) proceeds via the silylated ester.74 The silylation step is necessary because of the sensitive nature of allenyl acetates. A stereoselective total synthesis of isolobophytolide used BSA to convert an allylic pivalate into the corresponding enol trimethylsilyl derivative and this was then used in the intramolecular allylation of a sulfonyl acetate anion using Tetrakis(triphenylphosphine)palladium(0) as catalyst.75


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Harry Heaney

Loughborough University of Technology, UK



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