Silylation of carboxylic acids

A/,0-Bis(trimethylsilyl)trifluoroacetamide. This reagent is suitable for the silylation of carboxylic acids, alcohols, phenols, amides, and ureas. It has the advantage over bis(trimethylsilyl)acetamide in that the byproducts are more volatile. 

The use of HMDS (ca. 1.5 mmol) and saccharin (0.01 mmol) per mmol of substrate in refluxing dichloromethane or chloroform has been recommended (5) for easy silylation of carboxylic acids, including azetidin-2-one-4-carboxyIic acids. Clear solutions result, i.e., no ammonium salts are present at completion of the reaction, and consequently the silyl esters can be obtained by direct distillation, or merely by evaporation of solvent. 

Silylation of carboxylic acids.1 This reagent in the presence of sulfuric acid silvlates carboxylic acids in 75-95% isolated yield. The actual reagent may be bis(trimethylsilyl) sulfate, [(CH3).jSi]2SO.,. Several other acids are less effective as catalysts. 

Silylation of carboxylic acids.1 The reagent converts carboxylic acids into silyl carboxylates within 15-20 minutes in CC14 at 65-77° in the absence of a catalyst. The by-product is 2-oxazolidinone (insoluble in CC14). It is particularly useful for silylation of gem- or 1,2-dicarboxylic acids, which are easily decarboxylated when heated or in the presence of bases. 

A,0-Bis(trimethylsilyl)trifluoroacetamide. This reagent is suitable for the silylation of carboxylic acids, alcohols, phenols, amides, and ureas. It has the advantage over bis(trimethylsilyl)acetamide in that the by-products are more volatile. It has been used for the selective protection of 10-desacetyI-baccatin III using LHMDS as a catalyst. The TES and TBDMS ethers were prepared similarly. Conventional conditions using the silyl chloride results in silylation of the C-7 hydroxyl ... 

Uses Antifoam, emollient, antistat in cosmetics silylation of carboxylic acids endcapperfor silicones low polarity solvent coupling agent blocking agent lubricant release agent... 

The known disadvantage of TMS derivatives of amino acids is the easy postreaction hydrolysis of N-Si bonds in the formed derivatives, which leads to uncertainty regarding the formed products. At the same time, silylation of carboxylic acids is the most popular method for their derivatization (see Acids Derivatization for GC Analysis, p. 3). Hence, it seems reasonable to combine the silylation of CO2H groups in amino acids with the formation of other derivatives of amino groups, e.g., amides. This method of derivatization was realized only in 2007. " The first step is the formation of 0-TMS derivatives under mild conditions (with MSTFA as reagent), followed by trifluoroacetylation of amino groups by MBTFA (Fig. 5). 

Silylation of Carboxylic Acids. Alkanoic and aromatic carboxylic acids can be readily silylated with hexamethyldisiloxane. The reaction is carried out under acid catalysis (usually sulfuric acid) and azeotropic removal of water (eq 1). The rate of reaction is strongly influenced by the acidity of the carboxylic acid and increases with increased acidity. This method avoids the use of an amine and thus simplifies isolation of the product because it does not have to be separated from an amine hydrochloride. A limitation is the need for a solvent which allows for azeotropic removal of water. 

Some of the more common reagents for the conversion of carboxylic acids to trimethylsilyl esters are listed below. For additional methods that can be used to silylate acids, the section on alcohol protection should be consulted since many of the methods presented there are also applicable to carboxylic acids. Trimethylsilyl esters are cleaved in aqueous solutions. 

These can be prepared in good yield by reaction of either the mono-anions of trimethylsilyl carboxylates or, preferably, the dianions of carboxylic acids with TMSCI. Acetic and propionic acids give mixtures of O- and C-silylated products. 

The cationic pathway allows the conversion of carboxylic acids into ethers, acetals or amides. From a-aminoacids versatile chiral building blocks are accessible. The eliminative decarboxylation of vicinal diacids or P-silyl carboxylic acids, combined with cycloaddition reactions, allows the efficient construction of cyclobutenes or cyclohexadienes. The induction of cationic rearrangements or fragmentations is a potent way to specifically substituted cyclopentanoids and ring extensions by one-or four carbons. In view of these favorable qualities of Kolbe electrolysis, numerous useful applications of this old reaction can be expected in the future. 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

Carboxylic acids such as acetic acid react with alcohols such as methanol or with methoxytrimethylsilane 13 a in the presence of trimethylchlorosilane (TCS) 14 in THF or 2-methyl-THF to give esters such as methyl acetate in 97% yield and hex-amethyldisiloxane 7. Even methyl pivalate can be readily prepared in 91% yield [111]. Reaction of a variety of carboxylic acids, for example N-benzoylglycine 329, with two equivalents of yS-trimethylsilylethanol 330 and with 14 has been shown to afford esters such as 331 in 98% yield [112, 112 a]. Likewise, silylated carboxylic acids react with silylated alcohols or thiophenols in the presence of 4-trifluoro-methylbenzoic anhydride and TiCl4/AgCl04 to furnish esters or thioesters in high yields [113, 114] (Scheme 4.43). 

Whereas cycHzation of the cu-keto-co -hydroxyamide 1466 in boihng toluene or xylene in the presence of camphorsulfonic acid (CSA) results in decomposition of the starting material 1466, heating of 1466 with excess TMSOTf 20 and N-methyl-morphoHne in 1,2-dichloroethane affords 46% of the desired cycHzation product 1467 [30] (Scheme 9.16). The close relationship of product 1467 to d -oxazolines suggests that reaction of carboxylic acids 11 with free (or C-substituted) ethanola-mines 1468 and HMDS 2/TCS 14 might lead analogously, via the silylated intermediates 1469, to d -oxazolines 1470 and HMDSO 7. As demonstrated in the somewhat related cyclization of 1466 to 1467, combination of TMSOTf 20 with N-... 

Figure 7.6 Total ion current profile of the acidic fraction of a sample from a linseed oil reference paint layer (Opificio delle Pietre Dure, Florence, Italy), after saponification and silylation of carboxylic and hydroxyl ic groups [9]...

Because of the low-solubility of the hydroxyacid in cold CH2C12, it was treated with 1 equivalent of bis(trimethyl)silylacetamide, till the silylation of the acid functionality caused the solubilization of the starting compound. An ensuing standard Swern oxidation produced an uneventful oxidation of the alcohol, which was followed by a mild TMS carboxylate hydrolysis during the work-up. 

Protection of—COOH.1 Trimethylsilyl esters are useful for temporary protection of carboxylic acid groups during hydroboration of an unsaturated acid. The silyl esters need not be isolated and deprotection occurs spontaneously during the oxidation or iodination step. 

These derivatives of carboxylic acids behave analogously to ester silyl ketene acetals (Sedion... 

---