N-(t-Butyldimethylsilyl)-N-methyltrifluoroacetamide1

[77377-52-7]  · C9H18F3NOSi  · N-(t-Butyldimethylsilyl)-N-methyltrifluoroacetamide  · (MW 241.33)

(excellent t-butyldimethylsilylating reagent for alcohols, amines, carboxylates, thiols, and inorganic oxyanions;1,2 is often used to protect hydroxy and amino groups;1 derivatizing reagents for GC-MS analysis3)

Alternate Name: BSMTFA.

Physical Data: bp 168-170 °C; d 1.12 g cm-3.1

Solubility: sol most aprotic organic solvents.1

Form Supplied in: colorless liquid;1 neat or with 1% t-butyldimethylsilyl chloride commercially available.4,5

Preparative Method: obtained in 91% yield by reaction of N-methyl-2,2,2-trifluoroacetamide (1.0 equiv) in benzene and acetonitrile (1:1 v/v) with NaH (1.0 equiv) and then with t-BuMe2SiCl (1.2 equiv) at 4 °C.1

Handling, Storage, and Precautions: moisture-sensitive; is easily transferable with a gas-tight syringe.1

t-Butyldimethylsilylation of Functional Groups.1

In the presence of 1% of t-Butyldimethylchlorosilane as the catalyst, N-(t-butyldimethylsilyl)-N-methyltrifluoroacetamide (BSMTFA) functions as an extremely reactive t-butyldimethylsilylating reagent for alcohols, amines, carboxylic acids, and thiols. Silylation is generally completed within 5 min at 25 °C in acetonitrile.1 This amide is more reactive than N-(t-butyldimethylsilyl)-N-methylacetamide.

In the protection of a hydroxy group, the resultant t-butyldimethylsilyl (TBDMS) ethers are stable under the conditions for acetate saponification and hydrogenation.1 These silyl ethers also remain intact towards the Jones reagent and Wittig reagents. The TBDMS ethers are approx. 104 times more stable against hydrolysis than the corresponding trimethylsilyl (TMS) ethers.6 Selective removal of the TBDMS group can be accomplished by use of dilute acetic acid or Tetra-n-butylammonium Fluoride in THF at 25 °C.

Silylation of ketones by use of BSMTFA occurs in Triethylamine and DMF at 40-60 °C to give the corresponding silyl enol ethers in good to excellent yields (eq 1).7,8 In addition, silyl ether formation takes place in N-Hydroxysuccinimide (88% yield) and N-hydroxypyrrole (99% yield) by use of BSMTFA in THF.9

TBDMS amines are approx. 100 times more stable than the labile TMS ethers towards solvolysis.1 Reaction of dibenzyl aspartate with BSMTFA in acetonitrile and then with t-BuMgCl in ether affords an N-silylated b-lactam in 75% yield (eq 2).10 On the other hand, N-silylation of the sulfoximine PhMeS(=O)=NH proceeds in 92% yield with BSMTFA at 90 °C.11 The oxime and amide functionalities can also be silylated with BSMTFA (eq 3).12,13

Selective Silylation.

The bulkiness of the TBDMS group enables BSMTFA to possess greater selectivity than the corresponding TMS-containing agents in silylation. In general, t-butyldimethylsilylation of secondary amines, which are sterically more congested, proceeds more slowly than that of alcohols, carboxylates, thiols, and primary amines.1,4 Reaction of alkyldiamines with BSMTFA gives disilylated derivatives, in which each of the two primary amino groups is monosilylated. Trisilylation occurs after a prolonged reaction time.5 Selective monosilylation of a dihydroxy aromatic compound can be accomplished in 92% yield by use of 1.5 equiv of BSMTFA in a mixture of DMF and THF (eq 4).14

Derivatizing Reagent for GC-MS Analyses.

For organic compounds containing active protons (e.g. alcohols, amines, carboxylates, and thiols), silylation is often used to improve resolution and peak symmetry, or to decrease adsorption on the column for GC-MS analysis.3,15-17 Use of BSMTFA as the derivatizing reagent produces a mass spectrum with a prominent peak at M - 57 m/z, which represents loss of a t-butyl group from the molecular ion of the silylated species. In comparison, the trimethylsilylated amino acids are often unstable, easily hydrolyzed, and produce varying GC results.17

Silylation of Inorganic Oxyanions.2,18

The TBDMS derivatives of some inorganic oxyanions can be prepared by reaction of the corresponding free acids or the ammonium salts with BSMTFA in DMF. Those oxyanions include arsenate, arsenite, borate, carbonate, molybdenate, phosphate, phosphite, pyrophosphate, selenate, selenite, sulfate, sulfite, and vanadate. The t-butyldimethylsilylated inorganic oxyanions are relatively stable in comparison with the corresponding TMS derivatives, which show significant degradation on GC. Moreover, those t-butyldimethylsilylated oxyanions display single, sharp, and symmetrical chromatographic peaks without tailing on GC and produce easily interpretable mass spectra dominated by a characteristic M - 57 ion peak.


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Jih Ru Hwu & Keh-Loong Chen

National Tsing Hua University and Academia Sinica, Taiwan, Republic of China



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